Methods and kits for improving vascular health

ABSTRACT

The present invention provides methods and kits for improving or maintaining vascular health, including preventing myocardial infarction or stroke; maintaining or improving vascular reactivity; treating acute or chronic renal failure, peripheral arterial occlusive disease, coronary artery disease, or Raynaud&#39;s phenomenon; or lowering plasma levels of Lp(a) using an estrogen agonist/antagonist.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority of U. S. provisional applicationnumber 60/241,532, filed Oct. 17, 2000.

FIELD OF THE INVENTION

[0002] This invention relates to methods and kits for improving vascularhealth, including preventing myocardial infarction or stroke;maintaining or improving vascular reactivity; treating acute or chronicrenal failure, peripheral arterial occlusive disease, coronary arterydisease, or Raynaud's phenomenon; or lowering plasma levels of Lp(a)using an estrogen agonist/antagonist.

BACKGROUND OF THE INVENTION

[0003] The hormone estrogen has a profound effect in the vascular systemof both male and female subjects, although its administration isassociated with other effects that can be undesirable. Estrogenincreases vasodilatation and inhibits the response of blood vessels toinjury and the development of atherosclerosis. Estrogen-inducedvasodilatation occurs 5 to 20 minutes after estrogen has beenadministered and is not dependent on changes in gene expression; thisaction of estrogen is sometimes referred to as “nongenomic.” Theestrogen-induced inhibition of the response to vascular injury and thepreventive effect of estrogen against atherosclerosis occur over aperiod of hours or days after estrogen treatment and are dependent onchanges in gene expression in the vascular tissues; these actions aresometimes referred to as “genomic.”

[0004] In premenopausal women, 17β-estradioi produced by the ovaries isthe chief circulating estrogen. Serum estradiol concentrations are lowin preadolescent girls and increase at menarche. In women, they rangefrom about 100 pg per milliliter (367 pmol per liter) in the follicularphase to about 600 pg per milliliter (2200 pmol per liter) at the timeof ovulation. They may rise to nearly 20,000 pg per milliliter (70,000pmol per liter) during pregnancy. After menopause, serum estradiolconcentrations fall to values similar to or lower than those in men ofsimilar age (5 to 20 pg per milliliter [18 to 74 pmol per liter]) (Yen,S. S. C. and Jaffe, R. B., eds. Reproductive Endocrinology: Physiology,Pathophysiology and Clinical Management, 3rd ed. Philadelphia: W. B.Saunders, (1991)).

[0005] The ovaries are the principle source of estrogen in premenopausalwomen. The major secretory product is estradiol, synthesized bygranulosa cells from androgenic precursors provided by thecal cells.Secreted estradiol is oxidized reversibly to estrone, and both of theseestrogens can be converted to estriol. These transformations take placemainly in the liver, where interconversion between estrone and estradiolis catalyzed by 17-hydroxysteroid dehydrogenase.

[0006] In men and postmenopausal women, the principle source of estrogenis adipose tissue. In this and in other peripheral tissues, estrone issynthesized from dehydroepiandrosterone, which is secreted by theadrenal cortex. Thus, the contribution of adipose tissue estrogens isregulated, in part by the availability of androgenic precursors(Mendelson, C.R. and Simpson, E.R., Mol. Cell Endocrinol., 52:169-176,(1987)).

[0007] There are two estrogen receptors, estrogen receptor a andestrogen receptor β, both of which are members of the superfamily ofsteroid hormone receptors. (Walter, P., et al., Proc Nad Acad Sci USA1985;82:7889-93; Kuiper, G. G. J. M., et al; Proc NadAcad Sci USA1996;93:5925-30) Estrogen receptors α and β have considerable homologyand, like all steroid hormone receptors, are transcription factors thatalter gene expression when they are activated. (Walter, P., et al. ProcNad Acad Sci USA 1985;82:7889-93; Kuiper, G. G. J. M., et al.; Proc NadAcad Sci USA 1996;93:5925-30; Shibata, H., et al. Recent Prog Horm Res1997;52:141-65; Evans, R. M., Science 1988;240:889-95; Brown, M.,Hematol Oncol Clin North Am 1994;8:101-12). Blood vessels are complexstructures, with walls containing smooth-muscle cells and an endothelialcell lining. Vascular endothelial and smooth muscle cells bind estrogenwith high affinity (Mendelsohn, M. E., et al., Curr Opin Cardiol1994;9:619-26; Farhat, M. Y., et al., FASEB J 1996;10:615-24) andestrogen receptor α has been identified in both types of vascular cellsin women and men, (Karas, R. H., et al., Circulation 1994;89:1943-50;Losordo, D. W., et al., Circulation 1994;89:1501 -10; Venkov, C. D., etal., Circulation 1996;94:727-33; Kim-Schulze, S., et al., Circulation1996;94:1402-7; Caulin-Glaser, T., et al., J Clin Invest 1996;98:36-42)as well as in myocardial cells (Grohe, C., et al., FEBS Lett1997;416:107-12).

[0008] Estrogen receptor α activates specific target genes in vascularsmooth-muscle and endothelial cells (Table 1) (Karas, R. H., et al.,Circulation 1994;89:1943-50, Venkov, C. D., et al., Circulation1996;94:727-33; Kim-Schulze, S., et al, Circulation 1996;94:1402-7;Caulin-Glaser, T., et al., J Clin Invest 1996;98:36-42; Koike, H.,etal., J Vasc Surg 1996;23:477-82). Estrogen receptor β is structurallyand functionally distinct from estrogen receptor α. Functional estrogenreceptor β is also present in myocardial cells, in which it regulatesthe expression of nitric oxide synthases.

[0009] Estrogen alters serum lipid concentrations, coagulation andfibrinolytic systems, antioxidant systems, and the production of othervasoactive molecules, such as nitric oxide and prostaglandins, all ofwhich can influence the development of vascular disease.

[0010] The effects of estrogen therapy on serum lipid concentrationsresult largely from estrogen-receptor-mediated effects on the hepaticexpression of apoprotein genes (Table 1). Many studies, including onelarge, randomized, controlled trial (The Writing Group for the PEPITrial, JAMA 1995;273:199-208. [Erratum, JAMA 1995;274:1676.]) havedocumented that estrogen therapy in post-menopausal women decreasesserum total cholesterol and low density lipoprotein (LDL) cholesterolconcentrations, increases serum high-density lipoprotein (HDL)cholesterol and triglyceride concentrations, and decreases serum Lp(a)lipoprotein concentrations. Increased Lp(a) levels have been associatedwith increased risk of recurrent coronary heart disease events aftermenopause (Shlipak, M. G., et al., JAMA 2000;283: 1845-1852). Hepaticexpression of the genes for several coagulation and fibrinolyticproteins is also regulated by estrogen through estrogen receptors (Table1).

[0011] Estrogen directly regulates vasomotor tone through bothshort-term and long-term effects on the vasculature. Long-termadministration of estrogen is associated with decreased plasmaconcentrations of renin (Schunkert, H., et al., Circulation1997;95:39-45), angiotensin-converting enzyme (Proudler, A., et al.,Lancet 1995;346:89-90) and endothelin-1 (Ylikorkala, O., et al., J ClinEndocrinol Metab 1995;80:3384-7) and decreased vascular expression ofthe gene for angiotensin II receptor type 1 (Nickenig, G., et al.,Circulation 1998;97:2197-201) as well as an increased ratio of nitricoxide to endothelin-1 in plasma (Best, P. J. M., et al., Ann Intem Med1998;128:285-8). The net effect of these changes is to promotevasodilatation.

[0012] Estrogens can cause short-term vasodilatation by bothendothelium-dependent and endothelium-independent pathways. These rapideffects do not appear to involve changes in gene expression. Twomechanisms for the rapid vasodilatory effects of estrogens have beenexplored in some depth: effects on ion-channel function and effects onnitric oxide. At physiologic concentrations, estrogen stimulates theopening of calcium-activated potassium channels through a nitric oxide-and cyclic guanosine monophosphate- dependent pathway (White, R. E., etal., Circ Res 1995;77:936-42; Wellman, G. C., et al., Circ Res1996;79:1024-30) thus relaxing smooth muscle and promotingvasodilatation. These rapid effects of estrogen on vascular cells couldbe mediated by a known estrogen receptor, perhaps located in the plasmamembrane (Pappas, T. C., et al., FASEB J 1995;9:404-1 0) that is able toactivate nitric oxide synthase rapidly in a nongenomic manner. Thissuggestion is consistent with the observations that estrogen-inducedstimulation of nitric oxide synthase activity in endothelial cells isblocked by specific estrogen-receptor antagonists (Chen, Z., et al., JClin Invest 1 999;1 03:401-6; Lantin-Hermoso, R. L., Am J Physiol1997;273: LI 19-Ll 26; Caulin-Glaser, T., et al., Circ Res1997;81:885-92) and that estrogen receptor (X can directly activateendothelial nitric oxide synthase.

[0013] Estrogen rapidly causes coronary vasodilatation ex vivo(Mendelsohn, M. E., et al., Curr Opin Cardiol 1994;9:619-26; Farhat, M.Y., et al., FASEB J 1996;10:615-24) and in vivo in cholesterol-fedovariectomized primates (Williams, J. K., et al., J Am Coll Cardiol1992;20:452-7) and other animals (Guetta, V., et al., Circulation1997;96:2795-801). Estrogen dilates coronary and brachial arteries inpost-menopausal women (Reis, S. E., et al., Circulation 1994;89:52-60;Gilligan, D. M., et al., Circulation 1994;89:2545-51; Gilligan, D. M.,etal., Circulation 1994;90:786-91; Lieberman, E. H., etal., Ann InternMed 1994;121:936-41; Collins, P., et al., Circulation 1995;92:24-30;Guetta, V,, et al., Circulation 1997;96:2795-801) and, in some studies,in men (Collins, P., et al., Circulation 1995;92:24-30; Blumenthal,R.S., et al., Am J Cardiol 1997;80:1021-4; Reis, S. E., et al.,Circulation 1998;97:23-5). Sublingual administration of 17β-estradiol inpost-menopausal women increases the duration of treadmill exercisebefore the onset of ischemia (Rosano, G. M. C., etal., Lancet1993;342:133-6).

[0014] Estrogen increases the expression of genes for importantvasodilatory enzymes such as prostacyclin synthase and nitric oxidesynthase (Table 1) (Weiner, C. P., et al., Proc Natl Acad Sci USA1994;91;5212-6; Binko, J., et aL, Am J Physiol 1998;274:H853-H859). Someof the rapid effects of estrogen may therefore be due to longer-termincreases in the expression of the genes for these enzymes in vasculartissues. Estrogen may also increase the bioavailability of nitric oxidein vessels by increasing the expression of the gene for the inducibleform of nitric oxide synthase (Binko, J., et al., Am J Physiol1998;274:H853-H859). Long-term administration of estrogen increasesacetylcholine-mediated coronary vasodilatation in nonhuman primates(Williams, J. K., et al., Circulation 1990;81:1680-7; Williams, J. K.,et al, Circulation 1997;96:1970-5), male-to-female transsexuals(McCrohon, J. A., et al, J Am Coll Cardiol 1997;29:1432-6; New, G., etal, J Am Coll Cardiol 1997;29:1437-44), post-menopausal women(Herrington, D. M., et al, Am J Cardiol 1994;73: 951-2) andpost-menopausal women with angina and normal coronary arteries (Roque,M., et al, J Am Coll Cardiol 1 998;31 :139-43). TABLE 1ESTROGEN-REGULATED GENES OF POTENTIAL IMPORTANCE IN VASCULAR PHYSIOLOGYAND DISEASE. (Source: Mendelsohn, M. E. and Karas, R. H., N Engl J Med,1999; 340: 1801-11) PHYSIOLOGIC OR PATHO- GENE PRODUCT PHYSIOLOGIC ROLEEstrogen-regulated genes (vascular cells) Prostacyclin svnthaseVasodilatation Endothelial nitric oxide synthase VasodilatationInducible nitric oxide svnthase Vasodilatation in response to vascularinjury Endothelin-1 Vasoconstriction Collagen Vascular-matrix formationMatrix metalloproteinase 2 Vascular-matrix remodeling E-selectin Celladhesion Vascular-cell adhesion molecule Cell adhesion Vascularendothelial growth factor Angiogenesis and endothelial-cellproliferation Estrogen-regulated genes (nonvascular cells) Growth- anddevelopment-related genes Transforming growth factor β₁ Wound healingEpidermal growth factor receptor Cell growth in response to vascularinjury Platelet-derived growth factor Cell growth in response tovascular injury flt-4 tyrosine kinase Angiogenesis and endothelial-cellproliferation Coagulation- and fibrinolysis- related genes Tissue factorHemostasis in response to thrombosis Fibrinogen Hemostasis in responseto thrombosis Protein S Hemostasis in response to thrombosis Coagulationfactor VII Hemostasis in response to thrombosis Coagulation factor XIIHemostasis in response to thrombosis Plasminogen-activator inhibitor 1Hemostasis in response to thrombosis Tissue plasminogen activatorFibrinolysis Antithrombin III Anticoagulation Signaling-related andmiscellaneous genes Estrogen receptor α Hormonal regulation and geneexpression Estrogen receptor β Hormonal regulation and gene expressionMonocyte chemotactic protein 1 Monocyte recruitment and atherosclerosisI and HK2 (cardiac potassium Cardiac conduction channels) Connexin 43Cardiac conduction Leptin Fat metabolism and obesity Apolipoproteins A,B, D, and Lipid metabolism and atherosclerosis E and Lp(a)Angiotensin-converting enzyme Vasoconstriction Angiotensin II receptor,type 1 Vasoconstriction

[0015] Estrogen accelerates endothelial cell growth in vitro and in vivo(Morales, D. E., et al., Circulation 1995;91:755-63; Krasinski, K., etal., Circulation 1997;95:1768-72). The rapid re-endothelializationinduced by estrogen after vascular injury may be due in part toincreased local expression of vascular endothelial growth factor.Estrogen also inhibits apoptosis of cultured human endothelial cells inan estrogen receptor-dependent manner (Spyridopoulos, I., et al.,Circulation 1997;95:1505-14). Early restoration of endothelial integrityby estrogen may contribute to the attenuation of the response to injuryby increasing the availability of nitric oxide, which can directlyinhibit the proliferation of smooth-muscle cells (Cornwell, T. L., etal., Am J Physiol 1994;267:C1405-C1413). Estrogen directly inhibits themigration and proliferation of smooth-muscle cells in vitro (Kolodgic,F. D., et al., Am J Pathol 1996;148: 969-76; Bhalla, R. C., et a., Am JPhysiol 1997;272:H1996-H2003).

[0016] Thus, estrogen has both rapid and longer-term effects on theblood-vessel wall. It is believed that estrogen influences thebioavailability of endothelial-derived nitric oxide and, through nitricoxide-mediated increases in cyclic guanosine monophosphate, causes therelaxation of vascular smooth-muscle cells. The longer-term effects ofestrogen are due at least in part to changes in vascular-cell gene andprotein expression that is mediated by estrogen receptor α, β, or both.Estrogen-regulated proteins influence vascular function in an autocrineor paracrine fashion.

[0017] The direct effects of estrogen on the vasculature promotevasodilatation and inhibit the development and progression ofatherosclerosis. However, some of the nonvascular effects of estrogenmay offset its beneficial vascular effects.

[0018] Breast cancer is a hormone-dependent disease. Women withoutfunctioning ovaries who never receive estrogen replacement do notdevelop breast cancer. The female-to-male ratio for the disease is about150 to 1. A host of findings indicate that hormones play a critical roleas promoters of the disease. For most epithelial malignancies, a log-logplot of incidence versus age shows a straight-line increase with everyyear of life. A similar plot for breast cancer shows the same straightline increase, but with a decrease in slope beginning at the age ofmenopause. The three dates in a woman's life that have a major impact onbreast cancer incidence are age of menarche, age at first full-termpregnancy, and age of menopause. Women who experience menarche at age 16have only 50 to 60 percent of the lifetime breast cancer risk of womenwho experience menarche at age 12. Similarly, menopause occurring 10years before the median age (52 years), whether natural or surgicallyinduced, reduces lifetime breast cancer risk by about 35 percent.Compared with nulliparous women, women who have a first full-termpregnancy by age 18 have 30 to 40 percent the risk of breast cancer.Thus, length of menstrual life—particularly the fraction occurringbefore the first full-term pregnancy--is a substantial component of thetotal risk of breast cancer. This factor can account for 70 to 80percent of the variation in breast cancer frequency in differentcountries.

[0019] International variation has provided some of the most importantclues on hormonal carcinogenesis. A woman living to age 80 in NorthAmerica has 1 chance in 9 of developing invasive breast cancer. Asianwomen have one-fifth to one-tenth the risk of breast cancer of women inNorth America or Western Europe. Asian women have substantially lowerconcentrations of estrogens and progesterone. These differences cannotbe explained on a genetic basis, because Asian women living in a Westernenvironment have a risk identical to that of their Western counterparts.These women also differ markedly in height and weight from Asian womenin Asia; height and weight are critical regulators of age of menarcheand have substantial effects on plasma concentrations of estrogens.(Lippman, M. E., Breast Cancer, Chapter 91, in Harrison's Principles ofIntemal Medicine, 14th ed., 1998).

[0020] Menopause occurs naturally at an average age of 50 to 51 years inthe USA. As ovaries age, response to pituitary gonadotropins(follicle-stimulating hormone [FSH] and luteinizing hormone [LH])decreases, initially resulting in shorter follicular phases (thus,shorter menstrual cycles), fewer ovulations, decreased progesteroneproduction, and more irregularity in cycles. Eventually, the folliclefails to respond and does not produce estrogen. The transitional phase,during which a woman passes out of the reproductive stage, begins beforemenopause. It is termed the climacteric or perimenopause, although manypersons refer to it as menopause.

[0021] Premature menopause refers to ovarian failure of unknown causethat occurs before age 40. It may be associated with smoking, living athigh altitude, or poor nutritional status. Artificial menopause mayresult from oophorectomy, chemotherapy, radiation of the pelvis, or anyprocess that impairs ovarian blood supply.

[0022] Symptoms of the climacteric range from nonexistent to severe. Hotflushes (flashes) and sweating secondary to vasomotor instability affect75% of women. Most have hot flushes for more than 1 year, and 25 to 50%for more than 5 years. The woman feels warm or hot and may perspire,sometimes profusely. The skin, especially of the head and neck, becomesred and warm. The flush, which may last from 30 seconds to 5 minutes,may be followed by chills. Vasomotor symptoms of the hot flush coincidewith the onset of LH pulses, but not every increase in LH is associatedwith a hot flush, suggesting that hypothalamic control of LH pulses isindependent of that of flushes. This independence is confirmed by theoccurrence of hot flushes in women who have had pituitary failure and donot secrete LH and/or FSH.

[0023] Psychologic and emotional symptoms--including fatigue,irritability, insomnia, inability to concentrate, depression, memoryloss, headache, anxiety, and nervousness and timidity can occur. Sleepdisruption by recurrent hot flushes contributes to fatigue andirritability. Intermittent dizziness, paresthesias, palpitations, andtachycardia may also occur. Nausea, constipation, diarrhea, arthralgia,myalgia, cold hands and feet, and weight gain are also common.

[0024] The large reduction in estrogen leads to profound changes in thelower genital tract; e.g., the vaginal mucosa and vulvar skin becomethinner, the normal bacterial flora changes, and the labia minora,clitoris, uterus, and ovaries decrease in size. Inflammation of thevaginal mucosa (atrophic vaginitis) can cause the mucosa to have astrawberry appearance and can lead to urinary frequency and urgency,vaginal dryness, and dyspareunia. Women tend to lose pelvic muscle toneand to develop urinary incontinence, cystitis, and vaginitis.

SUMMARY OF THE INVENTION

[0025] The present invention provides methods of preventing myocardialinfarction or stroke; maintaining or improving vascular reactivity; ortreating acute or chronic renal failure, peripheral arterial occlusivedisease, coronary artery disease, or Raynaud's phenomenon, the methodscomprising administering to a patient at risk of having a myocardialinfarction or a stroke; in need of maintenance or improvement ofvascular reactivity; or having acute or chronic renal failure,peripheral arterial occlusive disease, coronary artery disease, orRaynaud's phenomenon, a therapeutically effective amount of an estrogenagonist/antagonist.

[0026] In a preferred embodiment of the methods, the estrogenagonist/antagonist is a compound of formula (I):

[0027] wherein:

[0028] A is selected from CH₂ and NR;

[0029] B, D and E are independently selected from CH and N;

[0030] Yis

[0031] (a) phenyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0032] (b) naphthyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0033] (c) C₃-C₈ cycloalkyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0034] (d) C₃-C₈ cycloalkenyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0035] (e) a five membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, -NR²- and —S(O)_(n)—,optionally substituted with 1-3 substituents independently selected fromR⁴;

[0036] (f) a six membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, -NR²- and —S(O)_(n)-optionally substituted with 1-3 substituents independently selected fromR⁴; or

[0037] (g) a bicyclic ring system consisting of a five or six memberedheterocyclic ring fused to a phenyl ring, said heterocyclic ringcontaining up to two heteroatoms selected from the group consisting of—O—, —NR²- and —S(O)_(n)-, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0038] Z¹ is

[0039] (a) —(CH₂)_(p) W(CH₂)_(q)-;

[0040] (b) —O(CH₂)_(p) CR⁵R⁶-;

[0041] (c) —O(CH₂)_(p)W(CH₂)_(q)-;

[0042] (d) —OCHR²CHR³-; or

[0043] (e) —SCHR²CHR³-;

[0044] G is

[0045] (a) —NR⁷R⁸;

[0046] wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or—CH₂—; optionally fused on adjacent carbon atoms with one or two phenylrings and, optionally independently substituted on carbon with one tothree substituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or

[0047] (c) a bicyclic amine containing five to twelve carbon atoms,either bridged or fused and optionally substituted with 1-3 substituentsindependently selected from R⁴; or

[0048] Z¹ and G in combination may be

[0049] W is

[0050] (a) —CH₂—;

[0051] (b) —CH═CH—;

[0052] (c) —O—;

[0053] (d) —NR² 13 ;

[0054] (e) —S(O)_(n)—;

[0055] (g) —CR²(OH)—;

[0056] (h) —CONR²—;

[0057] (i) —NR²CO—;

[0058] (k) —C═C—;

[0059] R is hydrogen or C₁—C₆ alkyl;

[0060] R² and R³ are independently

[0061] (a) hydrogen; or

[0062] (b) C₁-C₄ alkyl;

[0063] R⁴ is

[0064] (a) hydrogen;

[0065] (b) halogen;

[0066] (c) C₁—C6 alkyl;

[0067] (d) C₁—C₄ alkoxy;

[0068] (e) C₁—C₄ acyloxy;

[0069] (f) C₁—C₄ alkylthio;

[0070] (g) C₁—C₄ alkylsulfinyl;

[0071] (h) C₁—C₄ alkylsulfonyl;

[0072] (i) hydroxy (C₁—C₄)alkyl;

[0073] (j) aryl (C₁—C₄)alkyl;

[0074] (k) —CO₂H;

[0075] (l) —CN;

[0076] (m) —CONHOR;

[0077] (n) —SO₂NHR;

[0078] (o) —NH₂;

[0079] (p) C₁—C₄ alkylamino;

[0080] (q) C₁—C₄ dialkylamino;

[0081] (r) —NHSO₂R;

[0082] (s) —NO₂;

[0083] (t) -aryl; or

[0084] (u) —OH;

[0085] R⁵ and R⁶ are independently C₁—C₈ alkyl or together form a C₃—C₁₀carbocyclic ring;

[0086] R⁷ and R⁸ are independently

[0087] (a) phenyl;

[0088] (b) a C₃—C₁₀ carbocyclic ring, saturated or unsaturated;

[0089] (c) a C₃—C₁₀ heterocyclic ring containing up to two heteroatoms,selected from —O—, —N—and —S—;

[0090] (d) H;

[0091] (e) C₁—C₆ alkyl; or

[0092] (f) form a 3 to 8 membered nitrogen containing ring with R⁵ orR⁶;

[0093] R⁷ and R⁸ in either linear or ring form may optionally besubstituted with up to three substituents independently selected fromC₁-C₆ alkyl, halogen, alkoxy, hydroxy and carboxy;

[0094] a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring;

[0095] e is,lor 2;

[0096] m is 1, 2 or3;

[0097] n is 0, 1 or2;

[0098] p is 0, 1,2 or3;

[0099] q is 0, 1,2 or 3;

[0100] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0101] In another preferred embodiment of the methods, the estrogenagonist/antagonist is a compound of formula (IA)

[0102] R⁴ is H, OH, F, or Cl; and B and E are independently selectedfrom CH and N or an optical or geometric isomer thereof; or apharmaceutically acceptable salt, N-oxide, ester, quaternary ammoniumsalt, or a prodrug thereof.

[0103] In another preferred embodiment of the methods, the estrogenagonist/antagonist is(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olor an optical or geometric isomer thereof; a pharmaceutically acceptablesalt, N-oxide, ester, quatemary ammonium salt, or a prodrug thereof.

[0104] In another preferred embodiment of the methods, the estrogenagonist/antagonist is(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,D-tartrate salt.

[0105] In another preferred embodiment of the methods, the estrogenagonist/antagonist is a compound selected from the formulas V or VI:

[0106] wherein:

[0107] R_(1B) is selected from H, OH, —O—C(O)—C₁—C₁₂ alkyl (straightchain or branched), —O—C₁—C₁₂ alkyl (straight chain or branched orcyclic), or halogens or C₁—C₄ halogenated ethers;

[0108] R_(2B), R_(3B), R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH, —O—C(O)—C₁—C₁₂ (straight chain or branched),—O—C₁—C₁₂ (straight chain or branched or cyclic), halogens, or C₁—C₄halogenated ethers, cyano, C₁—C₆ alkyl (straight chain or branched), ortrifluoromethyl;

[0109] X_(A) is selected from H, C₁-C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0110] s is 2 or 3;

[0111] Y_(A) ; is the moiety:

[0112] wherein:

[0113] a) R_(7B) and R_(8B) are independently selected from the group ofH, C₁—C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl(straight chain or branched), C₁—C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; or

[0114] b) R_(7B) and R_(8B) are concatenated to form a five-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or

[0115] c) R_(7B) and R_(8B) are concatenated to form a six-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or

[0116] d) R_(7B) and R_(8B) are concatenated to form a seven-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄ alkyl)₂, —NHSO₂ R_(1B), NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or

[0117] e) R_(7B) and R_(8B) are concatenated to form an eight-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or

[0118] f) R_(7B) and R_(8B) are concatenated to form a saturatedbicyclic heterocycle containing from 6-12 carbon atoms either bridged orfused and containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁—C₄ alkyl,trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl, hydroxy(C₁—C₄)alkyl, —CO₂ H, —CN, —CONHR_(1B),

[0119] —NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄ alkyl)₂, -NHSO₂R_(1B),—NHCOR_(1B), —NO₂, or phenyl optionally substituted with 1-3 (C₁-C₄)alkyl;

[0120] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quatemary ammonium salt or prodrugthereof.

[0121] In another preferred embodiment of the methods, the estrogenagonist/antagonist is the compound TSE-424 of formula Va below:

[0122] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0123] In another preferred embodiment of the methods, the estrogenagonist/antagonist is EM-652 of formula III below or is EM-800 offormula IV below:

[0124] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0125] In another embodiment of the methods, a second compound that isuseful to prevent myocardial infarction or stroke; maintain or improvingvascular reactivity; or treat acute or chronic renal failure, peripheralarterial occlusive disease, coronary artery disease, or Raynaud'sphenomenon, is administered to the patient.

[0126] Also provided are methods of lowering the plasma concentration ofLp(a), the method comprising administering to a patient in need ofplasma Lp(a) lowering a therapeutically effective amount of an estrogenagonist/antagonist.

[0127] In a preferred embodiment of the methods, the estrogenagonist/antagonist is a compound of formula (I):

[0128] wherein:

[0129] A is selected from CH₂ and NR;

[0130] B,D and E are independently selected from CH and N;

[0131] Y is

[0132] (a) phenyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0133] (b) naphthyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0134] (c) C₃—C₈ cycloalkyl, optionally substituted with 1-2substituents independently selected from R ⁴;

[0135] (d) C₃—C₈ cycloalkenyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0136] (e) a five membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²- and —S(O)_(n)—,optionally substituted with 1-3 substituents independently selected fromR⁴;

[0137] (f) a six membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²- and —S(O)_(n)—optionally substituted with 1-3 substituents independently selected fromR⁴; or

[0138] (g) a bicyclic ring system consisting of a five or six memberedheterocyclic ring fused to a phenyl ring, said heterocyclic ringcontaining up to two heteroatoms selected from the group consisting of—O—, —NR²- and —S(O)_(n)—, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0139] z¹ is

[0140] (a) —(CH₂)_(p) W(CH₂)_(q)—;

[0141] (b) —O(CH₂)_(p) CR⁵R⁶—;

[0142] (c) —O(CH₂)_(p) W(CH₂)_(q)—;

[0143] (d) —OCHR²CHR³—; or

[0144] (e) —SCHR²CHR³—;

[0145] G is

[0146] (a) —NR⁷R⁸;

[0147] wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or—CH₂—; optionally fused on adjacent carbon atoms with one or two phenylrings and, optionally independently substituted on carbon with one tothree substituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or

[0148] (c) a bicyclic amine containing five to twelve carbon atoms,either bridged or fused and optionally substituted with 1-3 substituentsindependently selected from R⁴; or

[0149] Z¹ and G in combination may be

[0150] W is

[0151] (a) —CH₂—;

[0152] (b) —CH═CH—;

[0153] (c) —O—;

[0154] (d) —NR²—;

[0155] (e) —S(O)_(n)—;

[0156] (f)

[0157] (g) —CR²(OH)—;

[0158] (h) —CONR²;

[0159] (i) —NR²CO;

[0160] (k) —C≡C—;

[0161] R is hydrogen or C₁—C₆ alkyl;

[0162] R² and R³ are independently

[0163] (a) hydrogen; or

[0164] (b) C₁—C₄ alkyl;

[0165] R⁴ is

[0166] (a) hydrogen;

[0167] (b) halogen;

[0168] (c) C₁—C₆ alkyl;

[0169] (d) C₁—C₄ alkoxy;

[0170] (e) C₁—C₄ acyloxy;

[0171] (f) C₁—C₄ alkylthio;

[0172] (g) C₁—C₄ alkylsulfinyl;

[0173] (h) C₁—C4 alkylsulfonyl;

[0174] (i) hydroxy (C₁—C₄)alkyl;

[0175] (j) aryl (C₁—C₄)alkyl;

[0176] (k) —CO₂H;

[0177] (I) —CN;

[0178] (m) —CONHOR;

[0179] (n) —SO₂NHR;

[0180] (o) —NH₂;

[0181] (p) C₁—C₄ alkylamino;

[0182] (q) C₁—C₄ dialkylamino;

[0183] (r) —NHSO₂R;

[0184] (s) —NO₂;

[0185] (t) -aryl; or

[0186] (u) —OH;

[0187] R⁵ and R⁶ are independently C₁-C₈ alkyl or together form a C₃-C₁₀carbocyclic ring;

[0188] R⁷ and R⁸ are independently

[0189] (a) phenyl;

[0190] (b) a C₃—C₁₀ carbocyclic ring, saturated or unsaturated;

[0191] (c) a C₃—C₁₀ heterocyclic ring containing up to two heteroatoms,selected from —O—, —N—and —S—;

[0192] (d) H;

[0193] (e) C₁—C₆ alkyl; or

[0194] (f) form a 3 to 8 membered nitrogen containing ring with R⁵ orR⁶;

[0195] R⁷ and R⁸ in either linear or ring form may optionally besubstituted with up to three substituents independently selected fromC₁—C₆ alkyl, halogen, alkoxy, hydroxy and carboxy;

[0196] a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring;

[0197] e is 0,1 or 2;

[0198] m is 1,2 or 3;

[0199] n is 0, or,2;

[0200] p is 0,1,2o r3;

[0201] q is 0, 1, 2 or 3;

[0202] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0203] In another preferred embodiment of the methods, the estrogenagonist/antagonist is a compound of formula (IA):

[0204] R⁴ is H, OH, F, or Cl; and B and E are independently selectedfrom CH and N or an optical or geometric isomer thereof; or apharmaceutically acceptable salt, N-oxide, ester, quaternary ammoniumsalt, or a prodrug thereof.

[0205] In another preferred embodiment of the methods, the estrogenagonist/antagonist is(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yi-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomerthereof; a pharmaceutically acceptable salt, N-oxide, ester, quatemnaryammonium salt, or a prodrug thereof.

[0206] In another preferred embodiment of the methods, the estrogenagonist/antagonist is (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol, D-tartratesalt.

[0207] In another preferred embodiment of the methods, the estrogenagonist/antagonist is a compound selected from the formulas V or VI:

[0208] wherein:

[0209] R_(1B) is selected from H, OH, —O—C(O)—C₁—C₁₂ alkyl (straightchain or branched), —O—C₁—C₁₂ alkyl (straight chain or branched orcyclic), or halogens or C₁—C₄ halogenated ethers;

[0210] R_(2B), R_(3B), R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH, —O—C(O)—C₁—C₁₂ (straight chain or branched),—C₁—C₁₂ (straight chain or branched or cyclic), halogens, or C₁—C₄halogenated ethers, cyano, C₁—C₆ alkyl (straight chain or branched), ortrifluoromethyl;

[0211] X_(A) is selected from H, C₁—C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0212] s is 2or3;

[0213] Y_(A) is the moiety:

[0214] wherein:

[0215] a) R_(7B) and R_(8B) are independently selected from the group ofH, C₁—C₆ alkyl, or phenyl optionally substituted by CN, C₁—C₆ alkyl(straight chain or branched), C₁—C₈ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; or

[0216] b) R_(7B) and R_(8B) are concatenated to form a five-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or

[0217] c) R_(7B) and R_(8B) are concatenated to form a six-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or

[0218] d) R_(7B) and R_(8B) are concatenated to form a seven-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄ alkyl)₂, —NHSO₂ R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or

[0219] e) R_(7B) and R_(8B) are concatenated to form an eight-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or

[0220] f) R_(7B) and R_(8B) are concatenated to form a saturatedbicyclic heterocycle containing from 6-12 carbon atoms either bridged orfused and containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁—C₄ alkyl,trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄alkylthio, C₁—C₄C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl, hydroxy(C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁-C₄) alkyl;

[0221] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0222] In another preferred embodiment of the methods, the estrogenagonist/antagonist is the compound TSE-424 of formula Va below:

[0223] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0224] In another preferred embodiment of the methods, the estrogenagonist/antagonist is EM-652 of formula III below or is EM-800 offormula IV below:

[0225] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0226] In another preferred embodiment of the methods, a second compoundthat is useful to prevent myocardial infarction or stroke; maintain orimproving vascular reactivity; treat acute or chronic renal failure,peripheral arterial occlusive disease, coronary artery disease, orRaynaud's phenomenon; or lower plasma levels of Lp(a) is administered tothe patient.

[0227] Also provided by the present invention are kits for use by aconsumer to prevent myocardial infarction or stroke; maintain or improvevascular reactivity; treat acute or chronic renal failure, peripheralarterial occlusive disease, coronary artery disease, or Raynaud'sphenomenon; or lower plasma levels of Lp(a), the kits comprising:

[0228] (a) a pharmaceutical composition comprising an estrogenagonist/antagonist and a pharmaceutically acceptable carrier, vehicle ordiluent; and

[0229] (b) instructions describing a method of using the pharmaceuticalcomposition to prevent myocardial infarction or stroke; maintain orimprove vascular reactivity; treat acute or chronic renal failure,peripheral arterial occlusive disease, cornary artery disease orRaynaud's phenomenon; or lower plasma levels of Lp(a).

[0230] In a preferred embodiment of the kits, the estrogenagonist/antagonist is a compound of formula (I):

[0231] wherein:

[0232] A is selected from CH₂ and NR;

[0233] B, D and E are independently selected from CH and N;

[0234] Y is

[0235] (a) phenyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0236] (b) naphthyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0237] (c) C₃—C₈ cycloalkyl, optionally substituted with 1-2substituents independently selected from R₄;

[0238] (d) C₃—C₈ cycloalkenyl, optionally substituted with 1-2substituents independently selected from R ⁴;

[0239] (e) a five membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²- and —S(O)_(n)-,optionally substituted with 1-3 substituents independently selected fromR⁴;

[0240] (f) a six membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²- and —S(O)_(n)-optionally substituted with 1-3 substituents independently selected fromR⁴; or

[0241] (g) a bicyclic ring system consisting of a five or six memberedheterocyclic ring fused to a phenyl ring, said heterocyclic ringcontaining up to two heteroatoms selected from the group consisting of—O—, —NR²- and —S(O)_(n)-, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0242] Z¹ is

[0243] (a) —(CH₂)_(p) W(CH₂)_(q)-;

[0244] (b) —O(CH₂)_(p) CR⁵R⁶-;

[0245] (c) —O(CH₂)_(p)W(CH₂)_(q)-;

[0246] (d) —OCHR²CHR³; or

[0247] (e) —SCHR²CHR³-;

[0248] G is

[0249] (a) —NR⁷R⁸;

[0250] wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or—CH₂-; optionally fused on adjacent carbon atoms with one or two phenylrings and, optionally independently substituted on carbon with one tothree substituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or

[0251] (c) a bicyclic amine containing five to twelve carbon atoms,either bridged or fused and optionally substituted with 1-3 substituentsindependently selected from R⁴; or

[0252] Z¹ and G in combination may be

[0253] W is

[0254] (a) —CH₂-;

[0255] (b) —CH═CH—;

[0256] (c) —O—;

[0257] (d) —NR²-;

[0258] (e) —S(O)_(n)-;

[0259] (g) —CR²(OH)—;

[0260] (h) —CONR²—

[0261] (i) —NR²CO—;

[0262] (k) —C↑C—;

[0263] R is hydrogen or C₁—C₆ alkyl;

[0264] R² and R³ are independentiy

[0265] (a) hydrogen; or

[0266] (b) C₁—C₄ alkyl;

[0267] R⁴is

[0268] (a) hydrogen;

[0269] (b) halogen;

[0270] (c) C₁—C₆ alkyl;

[0271] (d) C₁—C₄ alkoxy;

[0272] (e) C₁—C₄ acyloxy;

[0273] (f) C₁—C₄ alkylthio;

[0274] (g) C₁—C₄ alkylsulfinyl;

[0275] (h) C₁—C₄ alkylsulfonyl;

[0276] (i) hydroxy (C₁—C₄)alkyl;

[0277] (j) aryl (C₁—C₄)alkyl;

[0278] (k) —CO₂H;

[0279] (l) —CN;

[0280] (m) —CONHOR;

[0281] (n) —SO₂NHR;

[0282] (o) —NH₂;

[0283] (p) C₁—C₄ alkylamino;

[0284] (q) C₁—C₄ dialkylamino;

[0285] (r) —NHSO₂R;

[0286] (s) —NO₂;

[0287] (t) —aryl; or

[0288] (u) —OH;

[0289] R⁵ and R⁶ are independently C₁—C₈ alkyl or together form a C₃—C₁₀carbocyclic ring;

[0290] R⁷ and R⁸ are independently

[0291] (a) phenyl;

[0292] (b) a C₃—C₁₀ carbocyclic ring, saturated or unsaturated;

[0293] (c) a C₃—C₁₀ heterocyclic ring containing up to two heteroatoms,selected from —O—, —N—and —S—;

[0294] (d) H;

[0295] (e) C₁—C₆ alkyl; or

[0296] (f) form a 3 to 8 membered nitrogen containing ring with R⁵or R⁶;

[0297] R⁷ and R⁸ in either linear or ring form may optionally besubstituted with up to three substituents independently selected fromC₁—C₆ alkyl, halogen, alkoxy, hydroxy and carboxy;

[0298] a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring;

[0299] e is 0, 1 or 2;

[0300] m is 1, 2 or 3;

[0301] n is 0, 1 or 2;

[0302] p is 0, 1, 2 or 3;

[0303] q is 0, 1, 2 or 3;

[0304] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0305] In another preferred embodiment of the kits, the estrogenagonist/antagonist is a compound of formula (IA):

[0306] wherein G is

[0307] R⁴ is H, OH, F, or Cl; and B and E are independently selectedfrom CH and N or an optical or geometric isomer thereof; or apharmaceutically acceptable salt, N-oxide, ester, quaternary ammoniumsalt, or a prodrug thereof.

[0308] In another preferred embodiment of the kits, the estrogenagonist/antagonist is(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof,or a pharmaceutically acceptable salt, N-oxide, ester, quaternaryammonium salt, or a prod rug thereof.

[0309] In another preferred embodiment of the kits, the estrogen agonistI antagonist is (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahyd ro-naphthalene-2-ol, D-tartratesalt.

[0310] In another preferred embodiment of the kits, the estrogenagonist/antagonist is a compound selected from the formulas V or VI:

[0311] wherein:

[0312] R_(1B) is selected from H, OH, —O—C(O)—C₁—C₁—C₁₂ alkyl (straightchain or branched), —O—C₁—C₁₂ alkyl (straight chain or branched orcyclic), or halogens or C₁—C₄ halogenated ethers;

[0313] R_(2B), R_(3B), R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH, —O—C(O)—C₁—C₁₂ (straight chain or branched),—O—C₁—C₁₂ (straight chain or branched or cyclic), halogens, or C₁-C₄halogenated ethers, cyano, C,-C₆ alkyl (straight chain or branched), ortrifluoromethyl;

[0314] X_(A) is selected from H, C₁—C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0315] s is 2 or 3;

[0316] Y_(A) is the moiety:

[0317] wherein:

[0318] a) R_(7B) and R_(8B) are independently selected from the group ofH, C₁—C₆ alkyl, or phenyl optionally substituted by CN, C₁—C₆ alkyl(straight chain or branched), C₁-C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; or

[0319] b) R_(7B) and R_(8B) are concatenated to form a five-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄ alkyl)₂, —NHSO₂RlB, —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or

[0320] c) R_(7B) and R_(8B) are concatenated to form a six-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C—C₄alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or

[0321] d) R_(7B) and R_(8B) are concatenated to form a seven-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or

[0322] e) R_(7B) and R_(8B) are concatenated to form an eight-memberedsaturated heterocycle containing one nitrogen heteroatom, theheterocycle being optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl,hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl),—N(Cl₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or

[0323] f) R_(7B) and R_(8B) are concatenated to form a saturatedbicyclic heterocycle containing from 6-12 carbon atoms either bridged orfused and containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁—C₄ alkyl,trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl, hydroxy(C₁—C₄)alkyl, —CO₂ H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄) alkyl; or an optical or geometric isomerthereof; or a pharmaceutically acceptable salt, N-oxide, ester,quaternary ammonium salt or prodrug thereof.

[0324] In another preferred embodiment of the kits, the estrogenagonist/antagonist is the compound TSE-424 of formula Va below:

[0325] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quatemary ammonium salt or prodrugthereof.

[0326] In another preferred embodiment of the kits, the estrogenagonist/antagonist is EM-652 of formula III below or EM-800 of formulaIV below:

[0327] or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.

[0328] In another preferred embodiment of the kits, the kits furthercomprises an additional compound that is useful to prevent myocardialinfarction or stroke; maintain or improve vascular reactivity; treatacute or chronic renal failure, peripheral arterial occlusive disease,coronary artery disease or Raynaud's phenomenon; or lower plasma levelsof Lp(a).

DETAILED DESCRIPTION OF THE INVENTION

[0329] This invention relates to methods and kits for improving ormaintaining vascular health, including preventing myocardial infarctionor stroke; maintaining or improving vascular reactivity; treating acuteor chronic renal failure, peripheral arterial occlusive disease,coronary artery disease, Raynaud's phenomenon; or lowering plasma levelsof Lp(a) using an estrogen agonist/antagonist.

[0330] The following terms are defined below:

[0331] The terms “treat”, “treatment”, and “treating” includepreventative (e.g., prophylactic) and palliative treatment or the act ofproviding preventative or palliative treatment.

[0332] The term “patient” means animals, particularly mammals. Preferredpatients are humans. Particularly preferred patients are postmenopausalwomen.

[0333] A patient in need of Lp(a) lowering is a patient who has a highplasma concentration of Lp(a). It is believed that a human patient whohas a plasma concentration of Lp(a) that is higher that about 30 mg/dLis in need of plasma Lp(a) lowering. “Adverse effects associated withestrogen” include breast tenderness, bloating, headache, increased bloodclotting and menstrual bleeding in women. Unopposed estrogen therapyincreases the risk of endometrial carcinoma. Women on long-term estrogentherapy may have an increased risk that is not reversed by concurrentprogestin (N Engl J Med 1995;332:1589).

[0334] The term “postmenopausal women” includes not only women ofadvanced age who have passed through menopause, but also women who havebeen hysterectomized or for some other reason have suppressed estrogenproduction, such as those who have undergone long-term administration ofcorticosteroids, suffer from Cushings'syndrome, or have gonadaldysgenesis.

[0335] “Breast cancer” is defined as a malignant proliferation ofepithelial cells lining the ducts or lobules of the breast.

[0336] An “estrogen agonist/antagonist” is a compound that affects someof the same receptors that estrogen does, but not all, and in someinstances, it antagonizes or blocks estrogen. It is also known as a“selective estrogen receptor modulator” (SERM). Estrogenagonists/antagonists may also be referred to as antiestrogens althoughthey have some estrogenic activity at some estrogen receptors. Estrogenagonists/antagonists are therefore not what are commonly referred to as“pure antiestrogens”. Antiestrogens that can also act as agonists arereferred to as Type I antiestrogens. Type I antiestrogens activate theestrogen receptor to bind tightly in the nucleus for a prolonged timebut with impaired receptor replenishment (Clark, et al., Steroids1973;22:707, Capony et al., Mol Cell Endocrinol, 1975;3:233).

[0337] Vascular reactivity relates to a blood vessel's ability to dilateand contract after presented with certain stimuli. The ability of ablood vessel to react appropriately to stimuli is important. Forexample, constriction of blood vessels during an ischemic event resultsin further ischemia and can exacerbate the damage caused by theischemia.

[0338] Stroke is one of the most common causes of death in the UnitedStates. The term cerebrovascular disease has also been used to describestroke. A stroke can comprise both ischemic events, which are typicallycaused by arteriosclerotic or hypertensive stenosis, thrombosis orembolism, and hemorrhagic events, which typically result in bleeding inthe brain tissue, the epidural, subdural or subarachnoid space, orcombinations thereof.

[0339] Myocardial infarction is also call heart attack. A heart attackoccurs when heart tissue is damaged by an inadequate supply of blood tothe heart tissue.

[0340] Peripheral arterial occlusive disease is typically defined asocclusion of the blood supply to the extremities by atheroscleroticplaques (atheromas), a thrombus, or an embolism.

[0341] Raynaud's phenomenon is a disease that is secondary to otherconditions and is characterized by spasms of the arterioles, usually inthe digits and occasionally in other acral parts such as the nose ortongue with intermittent pallor or cyanosis. Raynaud's phenomenon isprecipitated by exposure to cold or emotional upset. Frequently,paresthesia occurs.

[0342] The estrogen agonists/antagonists of the invention are effectivein improving or maintaining vascular health. By improving or maintainingvascular health, the methods and kits of the invention are suitable fortreating a variety of specific conditions. These conditions encompassmyocardial infarction, stroke, vascular reactivity, coronary arterydisease (CAD) such as atherosclerosis, acute and chronic renal failure,peripheral arterial occlusive disease, and Raynaud's phenomenon.

[0343] The estrogen agonists/antagonists of the invention are alsouseful in lowering serum lipoprotein (a) (Lp(a)) in a patient. Bylowering Lp(a), the risk of future coronary heart disease events islowered.

[0344] The estrogen agonists/antagonists of the invention may beadministered systemically or locally. For systemic use, the estrogenagonists and antagonists herein are formulated for parenteral (e.g.,intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal ortransdermal) or enteral (e.g., oral or rectal) delivery according toconventional methods. Intravenous administration can be by a series ofinjections or by continuous infusion over an extended period.Administration by injection or other routes of discretely spacedadministration can be performed at intervals ranging from weekly to onceto three or more times daily.

[0345] Preferred estrogen agonists/antagonists of the present inventioninclude the compounds described in U.S. Pat. No. 5,552,412. Thosecompounds are described by the formula designated herein as formula (I)given below:

[0346] wherein:

[0347] A is selected from CH₂ and NR;

[0348] B, D and E are independently selected from CH and N;

[0349] Y is

[0350] (a) phenyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0351] (b) naphthyl, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0352] (c) C₃—C₈ cycloalkyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0353] (d) C₃—C₈ cycloalkenyl, optionally substituted with 1-2substituents independently selected from R⁴;

[0354] (e) a five membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²- and —S(O)n—, optionallysubstituted with 1-3 substituents independently selected from R⁴;

[0355] (f) a six membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²- and —S(O)_(n)-optionally substituted with 1-3 substituents independently selected fromR⁴; or

[0356] (g) a bicyclic ring system consisting of a five or six memberedheterocyclic ring fused to a phenyl ring, said heterocyclic ringcontaining up to two heteroatoms selected from the group consisting of—O—, —NR²- and —S(O)_(n)-, optionally substituted with 1-3 substituentsindependently selected from R⁴;

[0357] Z¹ is

[0358] (a) —(CH₂)_(p) W(CH₂)_(q)-;

[0359] (b) —O(CH₂)_(p) CR⁵R⁶-;

[0360] (c) —O(CH₂)_(p) W(CH₂)_(q)-;

[0361] (d) —OCHR²CHR³-; or

[0362] (e) —SCHR²CHR³-;

[0363] G is

[0364] (a) —NR⁷R⁸;

[0365] wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or—CH₂—; optionally fused on adjacent carbon atoms with one or two phenylrings and, optionally independently substituted on carbon with one tothree substituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or

[0366] (c) a bicyclic amine containing five to twelve carbon atoms,either bridged or fused and optionally substituted with 1-3 substituentsindependently selected from R⁴; or

[0367] Z¹ and G in combination may be

[0368] W is

[0369] (a) —CH₂—;

[0370] (b) —CH=CH—;

[0371] (c) —O—;

[0372] (d) —NR²—;

[0373] (e) —S(O)_(n)-;

[0374] (g) —CR²(OH)—;

[0375] (h) —CONR²—;

[0376] (i) —NR²CO—;

[0377] (k) —C↑C—;

[0378] R is hydrogen or C₁—C₆ alkyl;

[0379] R² and R³ are independently

[0380] (a) hydrogen; or

[0381] (b) C₁—C₄ alkyl;

[0382] R⁴ is

[0383] (a) hydrogen;

[0384] (b) halogen;

[0385] (c) C₁—C₆ alkyl;

[0386] (d) C₁—C₄ alkoxy;

[0387] (e) C₁—C₄ acyloxy;

[0388] (f) C₁—C₄ alkylthio;

[0389] (g) C₁—C₄ alkylsulfinyl;

[0390] (h) C₁—C₄ alkylsulfonyl;

[0391] (i) hydroxy (C₁ 13 C₄)alkyl;

[0392] (j) aryl (C₁—C₄)alkyl;

[0393] (k) —CO₂H;

[0394] (l) —CN;

[0395] (m) —CONHOR;

[0396] (n) —SO₂NHR;

[0397] (o) —NH₂;

[0398] (p) C₁—C₄ alkylamino;

[0399] (q) C₁—C₄ dialkylamino;

[0400] (r) —NHSO₂R;

[0401] (s) —NO₂;

[0402] (t) —aryl; or

[0403] (u) —OH;

[0404] R⁵ and R⁶ are independently C₁—C₈ alkyl or together form a C₃—C₁₀carbocyclic ring;

[0405] R⁷ and R⁸ are independently

[0406] (a) phenyl;

[0407] (b) a C₃—C₁₀ carbocyclic ring, saturated or unsaturated;

[0408] (c) a C₃—C₁₀ heterocyclic ring containing up to two heteroatoms,selected from —O—, —N— and —S—;

[0409] (d) H;

[0410] (e) C₁—C₆ alkyl; or

[0411] (f) form a 3 to 8 membered nitrogen containing ring with R⁵ orR⁶;

[0412] R⁷ and R⁸ in either linear or ring form may optionally besubstituted with up to three substituents independently selected fromC₁—C₆ alkyl, halogen, alkoxy, hydroxy and carboxy;

[0413] a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring;

[0414] e is 0, 1 or 2;

[0415] m is 1, 2 or 3;

[0416] n is 0, 1 or 2;

[0417] p is 0, 1, 2 or 3;

[0418] q is 0, 1, 2 or 3;

[0419] and optical and geometric isomers thereof; and nontoxicpharmacologically acceptable acid addition salts, N-oxides, esters,quaternary ammonium salts and prodrugs thereof.

[0420] Additional preferred compounds of the invention also disclosed inU.S. Pat. No. 5,552,412 are described by the formula designated hereinas formula (IA):

[0421] R⁴ is H, OH, F, or Cl; and B and E are independently selectedfrom CH and N.

[0422] Especially preferred compounds for the methods and kits of theinvention are:

[0423] cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0424] (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0425] cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0426] cis-1 -[6′-pyrrolidinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;

[0427] 1 -(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0428] cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; and

[0429] 1-(4'-pyrrolidinoethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineand pharmaceutically acceptable salts thereof. An especially preferredsalt of(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olis the D-tartrate salt.

[0430] Other preferred estrogen agonists/antagonists are disclosed inU.S. Pat. 5,047,431. The structure of these compounds are described bythe formula designated herein as formula (II) below:

[0431] wherein

[0432] R^(1A) and R^(2A) may be the same or different and are either H,methyl, ethyl or a benzyl group; and optical or geometric isomersthereof; and pharmaceutically acceptable salts, N-oxides, esters,quaternary ammonium salts, and prodrugs thereof including droloxifene.

[0433] Additional preferred estrogen agonists/antagonists are tamoxifen:(ethanamine,2-[-4-(1,2-diphenyl-1 -butenyl)phenoxy]—N,N-dimethyl,(Z)-2-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)) and other compoundsas disclosed in U.S. Pat. No. 4,536,516; 4-hydroxy tamoxifen (i.e.,tamoxifen wherein the 2-phenyl moiety has a hydroxy group at the 4position) and other compounds as disclosed in U.S. Pat. No. 4,623,660;raloxifene: (methanone,[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-, hydrochloride) and other compounds as disclosed in U.S.Pat. Nos. 4,418,068; 5,393,763; 5,457,117; 5,478,847 and 5,641,790;toremifene: (ethanamine, 2-[4-(4-chloro-1,2-dipheny!-l-butenyl)phenoxy]—N,N-dimethyl-, (Z)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) and other compounds as disclosed inU.S. Pat. Nos. 4,696,949 and 4,996,225; centchroman:1-[2-[[4-(-methoxy-2,2,dimethyl-3-phenyl-chroman4-yl)-phenoxy]-ethyl]-pyrrolidine and othercompounds as disclosed in U.S. Pat. No. 3,822,287; idoxifene:pyrrolidine, 1-[-[4-[[1 -(4-iodophenyl)-2-phenyl-1-butenyl]phenoxy]ethyl] and other compounds as disclosed in U.S. Pat.No. 4,839,155;6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol and other compounds as disclosed in U.S. Pat. Nos. 5,484,795; and{4-[2-(2-aza-bicyclo[2.2.I]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone and other compounds as disclosed inpublished international patent application WO 95/10513. Other preferredcompounds include GW 5638 and GW 7604. The synthesis of these compoundsis described in Willson et al., J. Med. Chem., 1994;37:1550-1552.

[0434] Further preferred estrogen agonists/antagonists include EM-652(as shown in the formula designated herein as formula (III) and EM-800(as shown in the formula designated herein as formula (IV)). Thesynthesis of EM-652 and EM-800 and the activity of various enantiomersis described in Gauthier et al., J. Med. Chem., 1997;40:2117-2122.

[0435] Further preferred estrogen agonists I antagonists include TSE 424and other compounds disclosed in U.S. Pat. No. 5,998,402, U.S. Pat. No.5,985,910, U.S. Pat. No. 5,780,497, U.S. Pat. No. 5,880,137, andEuropean Patent Application EP 0802183 A1 including the compoundsdescribed by the formulae designated herein as formulae V and VI, below:

[0436] wherein:

[0437] R_(1B) is selected from H, OH or the C₁-C₁₂ esters (straightchain or branched) or C₁—C₁₂ (straight chain or branched or cyclic)alkyl ethers thereof, or halogens; or C₁—C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether.

[0438] R_(2B), R₃B, R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH or the C₁—C₁₂ esters (straight chain or branched) orC₁—C₁₂ alkyl ethers (straight chain or branched or cyclic) thereof,halogens, or C₁—C₄ halogenated ethers including trifluoromethyl etherand trichloromethyl ether, cyano, C₁—C₆ alkyl (straight chain orbranched), or trifluoromethyl;

[0439] X_(A) is selected from H, C₁—C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0440] s is2or3;

[0441] Y_(A) is selected from:

[0442] a) the moiety:

[0443] wherein R_(7B) and R_(8B) are independently selected from thegroup of H, C₁—C₆ alkyl, or phenyl optionally substituted by CN, C₁—C₆alkyl (straight chain or branched), C₁—C₆ alkoxy (straight chain orbranched), halogen, —OH, —CF₃, or —OCF₃;

[0444] b) a five-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁—C₄ alkyl)-, —N═, and—S(O)_(u)—, wherein u is an integer of from 0-2, optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, C₁—C₄ alkylamino, di(C₁—C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, and phenyl optionally substituted with 1-3 (C₁—C₄)alkyl;

[0445] c) a six-membered saturated, unsaturated or partially unsaturatedheterocycle containing up to two heteroatoms selected from the groupconsisting of —O—, —NH—, —N(C₁—C₄ alkyl)-, —N═, and —S(O)_(u)-, whereinu is an integer of from 0-2, optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C0—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, C₁—C₄ alkylamino, di(C₁—C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, and phenyl optionally substituted with 1-3 (C₁—C₄)alkyl;

[0446] d) a seven-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁—C₄ alkyl)-, —N═, and—S(O)_(u)-, wherein u is an integer of from 0-2, optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B,)—NH₂,C₁—C₄ alkylamino, di(C₁—C₄)alkylamino, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂,and phenyl optionally substituted with 1-3 (C₁—C₄)alkyl; or

[0447] e) a bicyclic heterocycle containing from 6-12 carbon atomseither bridged or fused and containing up to two heteroatoms selectedfrom the group consisting of —O—, —NH—, —N(C₁—C₄ alkyl)-, and—S(O)_(u)-, wherein u is an integer of from 0-2, optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, Cl—C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —N═, C₁—C₄ alkylamino, di(C₁—C₄)alkylamino, —NHSO₂R_(1B),—NHCOR_(1B), —NO₂, and phenyl optionally substituted with 1-3 (C₁—C₄)alkyl; and optical and geometric isomers thereof; and nontoxicpharmacologically acceptable acid addition salts, N-oxides, esters,quaternary ammonium salts, and prodrugs thereof.

[0448] The more preferred compounds of this invention are those havingthe general structures V or VI, above, wherein:

[0449] R_(1B) is selected from H, OH or the C₁—C₁ ₂ esters or alkylethers thereof, and halogen;

[0450] R_(2B), R_(3B), R_(4B), R_(5B), and R_(6B) are independentlyselected from H, OH or the C_(1—C) ₁₂ esters or alkyl ethers thereof,halogen, cyano, C₁—C₆ alkyl, or trihalomethyl, preferablytrifluoromethyl, with the proviso that, when R_(1B) is H, R_(2B) is notOH;

[0451] X_(A) is selected from H, C₁—C₆ alkyl, cyano, nitro,trifluoromethyl, and halogen;

[0452] Y_(A) is the moiety:

[0453] R_(7B) and R_(8B) are selected independently from H, C₁—C₆ alkyl,or combined by —(CH₂)_(W)-, wherein w is an integer of from 2 to 6, soas to form a ring, the ring being optionally substituted by up to threesubstituents selected from the group of hydrogen, hydroxyl, halo, C₁—C₄alkyl, trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄ alkylthio,C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H,—CN, —CONH(C₁—C₄alkyl), —NH₂, C₁—C₄ alkylamino, C₁—C₄ dialkylamino,—NHSO₂(C₁—C₄alkyl), —CO(C₁—C₄alkyl), and —NO₂; and optical and geometricisomers thereof; and nontoxic pharmacologically acceptable acid additionsalts, N-oxides, esters, quaternary ammonium salts, and prodrugsthereof.

[0454] The rings formed by a concatenated R_(7B) and R_(8B), mentionedabove, may include, but are not limited to, aziridine, azetidine,pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneaminerings.

[0455] The most preferred compounds of structural formulas V and VI,above, are those wherein R_(1B) is OH; R_(2B)-R_(6B) are as definedabove; X_(A) is selected from the group of Cl, NO₂, CN, CF₃, or CH₃;Y_(A) is the moiety

[0456] and R_(7B) and R_(8B) are concatenated together as —(CH₂)_(t)-,wherein t is an integer of from 4 to 6, to form a ring optionallysubstituted by up to three subsituents selected from the group ofhydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄alkylsulfonyl, hydroxy (C₁-C₄) alkyl, —CO₂H, —CN, —CONH(C₁—C₄)alkyl,—NH₂, C₁—C₄ alkylamino, di(C₁—C₄) alkylamino, —NHSO₂(C₁—C₄)alkyl,—NHCO(C₁—C₄)alkyl, and —NO₂; and optical and geometric isomers thereof;and nontoxic pharmacologically acceptable acid addition salts, N-oxides,esters, quaternary ammonium salts, and prodrugs thereof. Anotherpreferred compound is TSE-424 as described by the formula designatedherein as formula (Va) below:

[0457] The pharmaceutically acceptable acid addition salts of theestrogen agonists/antagonists of this invention may be formed of thecompound itself, or of any of its esters, and include thepharmaceutically acceptable salts which are often used in pharmaceuticalchemistry. For example, salts may be formed with inorganic or organicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfonic acids including such agents as naphthalenesulfonic,methanesulfonic and toluenesulfonic acids, sulfuric acid, nitric acid,phosphoric acid, tartaric acid, pyrosulfuric acid, metaphosphoric acid,succinic acid, formic acid, phthalic acid, lactic acid and the like,most preferable with hydrochloric acid, citric acid, benzoic acid,maleic acid, acetic acid or propionic acid.

[0458] The estrogen agonists/antagonists of this invention, as discussedabove, can be administered in the form of pharmaceutically acceptablesalts. The salts are conveniently formed, as is usual in organicchemistry, by reacting the compound of this invention with a suitableacid, such as has been described above. The salts are quickly formed inhigh yields at moderate temperatures, and often are prepared by merelyisolating the compound from a suitable acidic wash as the final step ofthe synthesis. The salt-forming acid is dissolved in an appropriateorganic solvent, or aqueous organic solvent, such as an alkanol, ketoneor ester. On the other hand, if the compound of this invention isdesired in the free base form, it is isolated from a basic final washstep, according to the usual practice. A preferred technique forpreparing hydrochlorides is to dissolve the free base in a suitablesolvent and dry the solution thoroughly, as over molecular sieves,before bubbling hydrogen chloride gas through it. A preferred salt of(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-olis the D-(-)-tartrate salt. It will also be recognized that it ispossible to administer amorphous forms of the estrogenagonists/antagonists.

[0459] The expression “pharmaceutically acceptable salts” includes bothpharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable cationic salts. The expression “pharmaceutically-acceptablecationic salts” is intended to define but is not limited to such saltsas the alkali metal salts, (e.g. sodium and potassium), alkaline earthmetal salts (e.g., calcium and magnesium), aluminum salts, ammoniumsalts, and salts with organic amines such as benzathine(N,N′-dibenzylethylenediamine), choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), benethamine(N-benzylphenethylamine), diethylamine, piperazine, tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol) and procaine. The expression“pharmaceutically-acceptable acid addition salts” is intended to definebut is not limited to such salts as the hydrochloride, hydrobromide,sulfate, hydrogen sulfate, phosphate, hydrogen phosphate,dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate(mesylate) and ptoluenesulfonate (tosylate) salts.

[0460] One of ordinay skill in the art will recognize that certainestrogen agonists/antagonists of this invention will contain one or moreatoms which may be in a particular stereochemical, tautomeric, orgeometric configuration, giving rise to stereoisomers, tautomers andconfigurational isomers. All such tautomers and isomers and mixturesthereof are included in this invention. Hydrates and solvates of thecompounds of this invention are also included.

[0461] The subject invention also includes isotopically-labeled estrogenagonists/antagonists, which are structurally identical to thosedisclosed above, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number usually found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸Fand ³⁶CI, respectively. Compounds of the present invention, prodrugsthereof, and pharmaceutically acceptable salts of said compounds and ofsaid prodrugs which contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of this invention. Certainisotopically labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out known or referenced proceduresand by substituting a readily available isotopically labeled reagent fora non-isotopically labeled reagent.

[0462] Those of ordinary skill in the art will recognize thatphysiologically active compounds which have accessible hydroxy groupscan be administered in the form of pharmaceutically acceptable esters.The compounds of this invention can be effectively administered as anester, formed on the hydroxy groups, just as one skilled inpharmaceutical chemistry would expect. It is possible, as has long beenknown in pharmaceutical chemistry, to adjust the rate or duration ofaction of the compound by appropriate choices of ester groups.

[0463] Certain ester groups are preferred when a compound of thisinvention contains an ester. The estrogen agonists/antagonists includingthe compounds of formula I, IA, II, III, IV, V, Va, or VI may containester groups at various positions as defined herein above, where thesegroups are represented as —COOR⁹, R⁹ is C₁—C₁₄ alkyl, C₁—C₃ chloroalkyl,C₁—C₃ fluoroalkyl, C₅ —C₇ cycloalkyl, phenyl, or phenyl mono- ordisubstituted with C₁—C₄ alkyl, C₁—C₄ alkoxy, hydroxy, nitro, chloro,fluoro or tri(chloro or fluoro)methyl.

[0464] As used herein, the term “effective amount” means an amount ofcompound that is capable of treating the described pathologicalconditions. The specific dose of a compound administered according tothis invention will, of course, be determined by the particularcircumstances surrounding the case including, for example, the compoundadministered, the route of administration, the state of being of thepatient, and the severity of the pathological condition being treated.

[0465] The dose of a compound of this invention to be administered to asubject is rather widely variable and subject to the judgement of theattending physician. It should be noted that it may be necessary toadjust the dose of a compound when it is administered in the form of asalt, such as a laureate, the salt forming moiety of which has anappreciable molecular weight.

[0466] The following dosage amounts and other dosage amounts set forthelsewhere in this description and in the appendant claims are for anaverage human subject having a weight of about 65 kg to about 70 kg. Theskilled practitioner will readily be able to determine the dosage amountrequired for a subject whose weight falls outside the 65 kg to 70 kgrange, based upon the medical history of the subject. All doses setforth herein, and in the appendant claims, are daily doses of the freebase form of the estrogen agonists/antagonists. Calculation of thedosage amount for other forms of the free base form such as salts orhydrates is easily accomplished by performing a simple ratio relative tothe molecular weights of the species involved.

[0467] The general range of effective administration rates of theestrogen agonists/antagonists is from about 0.001 mg/day to about 200mg/day. A preferred rate range is from about 0.010 mg/day to about 100mg/day. Of course, it is often practical to administer the daily dose ofcompound in portions, at various hours of the day. However, in any givencase, the amount of compound administered will depend on such factors asthe potency of the specific estrogen agonist/antagonist, the solubilityof the compound, the formulation used and the route of administration.

[0468] Methods of formulation are well known in the art and aredisclosed, for example, in Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 19th Edition (1995). Pharmaceuticalcompositions for use within the present invention can be in the form ofsterile, non-pyrogenic liquid solutions or suspensions, coated capsules,suppositories, lyophilized powders, transdermal patches or other formsknown in the art.

[0469] Capsules are prepared by mixing the compound with a suitablediluent and filling the proper amount of the mixture in capsules. Theusual diluents include inert powdered substances such as starch of manydifferent kinds, powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

[0470] Tablets are prepared by direct compression, by wet granulation,or by dry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0471] A lubricant may be necessary in a tablet formulation to preventthe tablet and punches from sticking in the die. The lubricant is chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils.

[0472] Tablet disintegrators are substances which facilitate thedisintegration of a tablet to release a compound when the tablet becomeswet. They include starches, clays, celluloses, algins and gums, moreparticularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose,for example, may be used as well as sodium lauryl sulfate.

[0473] Tablets are often coated with sugar as a flavorant and sealant,or with film-forming protecting agents to modify the dissolutionproperties of the tablet. The compounds may also be formulated aschewable tablets, by using large amounts of pleasant-tasting substancessuch as mannitol in the formulation, as is now well-established in theart.

[0474] When it is desired to administer a compound as a suppository, thetypical bases may be used. Cocoa butter is a traditional suppositorybase, which may be modified by addition of waxes to raise its meltingpoint slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

[0475] The effect of the compounds may be delayed or prolonged by properformulation. For example, a slowly soluble pellet of the compound may beprepared and incorporated in a tablet or capsule. The technique may beimproved by making pellets of several different dissolution rates andfilling capsules with a mixture of the pellets. Tablets or capsules maybe coated with a film which resists dissolution for a predictable periodof time. Topical formulations may be designed to yield delayed and/orprolonged percutaneous absorption of a compound. Even the parenteralpreparations may be made long-acting, by dissolving or suspending thecompound in oily or emulsified vehicles which allow it to disperse onlyslowly in the serum.

[0476] The term “prodrug” means a compound that is transformed in vivoto yield a compound of the present invention. The transformation mayoccur by various mechanisms, such as through hydrolysis in blood. Adiscussion of the use of prodrugs is provided by T. Higuchi and W.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

[0477] For example, if a compound of the present invention contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as (C₁—C₈)alkyl, (C₂-C₁₂) alkanoyloxymethyl, l-(alkanoyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl havingfrom 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6carbon atoms, 1-(alkoxycarbonyloxy) ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy) ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl) amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁—C₂)alkylamino(C₂—C₃)alkyl (such as P-dimethylaminoethyl),carbamoyl-(C₁—C₂)alkyl, N,N-di(C₁—C₂) alkylcarbamoyl-(C₁—C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂—C₃) alkyl.

[0478] Similarly, if a compound of the present invention comprises analcohol functional group, a prodrug can be formed by the replacement ofthe hydrogen atom of the alcohol group with a group such as(C₁—C₆)alkanoyloxymethyl, 1—((C₁—C₆) alkanoyloxy)ethyl,1-methyl-1—((C₁—C₆)alkanoyloxy)ethyl, (C₁—C₆) alkoxycarbonyloxymethyl,N—(C₁—C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁—C₆) alkanoyl,α-amino(C₁—C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring α-amino acids, P(O)(OH)₂,—P(O)(O(C₁—C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0479] If a compound of the present invention comprises an aminefunctional group, a prodrug can be formed by the replacement of ahydrogen atom in the amine group with a group such as R^(X)-carbonyl,R^(X)O-carbonyl, NR^(X)R^(X)′-carbonyl

[0480] where R^(X) and R^(X)′ are each independently (C₁—C₁₀)alkyl,(C₃—C₇)cycloalkyl, benzyl, or R^(X)-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl-natural α-aminoacyl, —C(OH) C(O)OY^(X) whereinY^(X1) is H, (C₁—C₆)alkyl or benzyl, —C(OY^(X0)) Y^(X1) wherein Y^(X0)is (C₁—C₄) alkyl and Y^(X1) is (C₁—C₆)alkyl, carboxy(C₁—Ce)alkyl,amino(C₁—C₄)alkyl or mono-N— or di-N,N—(C₁—C₆)alkylaminoalkyl,—C(Y^(X2)) Y^(X3) wherein Y^(X2) is H or methyl and y^(X3) is mono-N— ordi-N,N—(C₁—C₆)alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

[0481] Advantageously, the present invention also provides kits for useby a consumer to prevent myocardial infarction or stroke; maintain orimprove vascular reactivity; treat acute or chronic renal failure,peripheral arterial occlusive disease, coronary artery disease, orRaynaud's phenomenon; or lower plasma levels of Lp(a). The kits comprisea) a pharmaceutical composition comprising an estrogenagonist/antagonist and a pharmaceutically acceptable carrier, vehicle ordiluent; and b) instructions describing a method of using thepharmaceutical compositions to prevent myocardial infarction or stroke;maintain or improve vascular reactivity; treat acute or chronic renalfailure, peripheral arterial occlusive disease, coronary artery disease,or Raynaud's phenomenon; or lower plasma levels of Lp(a). Theinstructions may also indicate that the kit is to improve or maintainvascular health and/or lower serum lipoprotein (a) levels whilesubstantially reducing the concomitant liability of adverse effectsassociated with estrogen administration.

[0482] A “kit'as used in the instant application includes a containerfor containing the pharmaceutical compositions and may also includedivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container employed can depend on the exact dosage form involved, forexample a conventional cardboard box would not generally be used to holda liquid suspension. It is feasible that more than one container can beused together in a single package to market a single dosage form. Forexample, tablets may be contained in a bottle, which is in turncontained within a box.

[0483] An example of such a kit is a so-called blister pack. Blisterpacks are well known in the packaging industry and are being widely usedfor the packaging of pharmaceutical unit dosage forms (tablets,capsules, and the like). Blister packs generally consist of a sheet ofrelatively stiff material covered with a foil of a preferablytransparent plastic material. During the packaging process, recesses areformed in the plastic foil. The recesses have the size and shape ofindividual tablets or capsules to be packed or may have the size andshape to accommodate multiple tablets and/or capsules to be packed.Next, the tablets or capsules are placed in the recesses accordingly andthe sheet of relatively stiff material is sealed against the plasticfoil at the face of the foil which is opposite from the direction inwhich the recesses were formed. As a result, the tablets or capsules areindividually sealed or collectively sealed, as desired, in the recessesbetween the plastic foil and the sheet. Preferably the strength of thesheet is such that the tablets or capsules can be removed from theblister pack by manually applying pressure on the recesses whereby anopening is formed in the sheet at the place of the recess. The tablet orcapsule can then be removed via said opening.

[0484] It may be desirable to provide a written memory aid, where thewritten memory aid is of the type containing information and/orinstructions for the physician, pharmacist or subject, e.g., in the formof numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested or a card which contains the same type ofinformation. Another example of such a memory aid is a calendar printedon the card e.g., as follows “First Week, Monday, Tuesday,” . . . etc .. . . “Second Week, Monday, Tuesday, . . . ” etc. Other variations ofmemory aids will be readily apparent. A “daily dose” can be a singletablet or capsule or several tablets or capsules to be taken on a givenday.

[0485] Another specific embodiment of a kit is a dispenser designed todispense the daily doses one at a time. Preferably, the dispenser isequipped with a memory-aid, so as to further facilitate compliance withthe regimen. An example of such a memory-aid is a mechanical counterwhich indicates the number of daily doses that has been dispensed.Another example of such a memory-aid is a battery-powered micro-chipmemory coupled with a liquid crystal readout, or audible reminder signalwhich, for example, reads out the date that the last daily dose has beentaken and/or reminds one when the next dose is to be taken.

[0486] The kits and methods of the present invention may also include,in addition to an estrogen agonist/antagonist, one or more additionalpharmaceutically active compounds. Preferably, any additional compoundis an estrogen agonist/antagonist or another compound that is useful toprevent myocardial infarction or stroke; maintain or improving vascularreactivity; or treat acute or chronic renal failure, peripheral arterialocclusive disease, coronary artery disease, or Raynaud's phenomenon.Moreover, the additional compound can also be another compound thatlowers the plasma concentration of Lp(a) in a patient. Compounds thatare used to treat stroke include anticoagulants such as heparin andantiplatelet drugs such as aspirin and ticlopidine.

[0487] In addition, an estrogen agonist/antagonist can be administeredin combination with other pharmaceutical agents such as cholesterolbiosynthesis inhibitors and cholesterol absorption inhibitors,especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors,HMG-CoA reductase and synthase gene expression inhibitors, CETPinhibitors, biles acid sequesterants, fibrates, ACAT inhibitors,squalene synthetase inhibitors, anti-oxidants and niacin. The estrogenagonists/antagonists of the present invention may also be administeredin combination with naturally occurring compounds that act to lowerplasma cholesterol levels. These naturally occurring compounds arecommonly called nutraceuticals and include, for example, garlic extract,Benecol®, and niacin.

[0488] Specific cholesterol absorption inhibitors and cholesterolbiosynthesis inhibitors are described in detail below. Additionalcholesterol absorption inhibitors are known to those skilled in the artand are described, for example, in PCT WO 94/00480.

[0489] Any HMG-CoA reductase inhibitor may be employed as an additionalcompound in the combination therapy aspect of the present invention. Theterm HMG-CoA reductase inhibitor refers to a compound that inhibits thebiosynthesis of hydroxymethylglutaryl-coenzyme A to mevalonic acid ascatalyzed by the enzyme HMG-CoA reductase. Such inhibition may bedetermined readily by one of skill in the art according to standardassays (e.g., Methods of Enzymology, 71: 455-509 (1981); and thereferences cited therein). A variety of these compounds are describedand referenced below. U.S. Pat. No. 4,231,938 discloses certaincompounds isolated after cultivation of a microorganism belonging to thegenus Aspergillus, such as lovastatin. Also, U.S. Pat. No. 4,444,784discloses synthetic derivatives of the aforementioned compounds, such assimvastatin. Additionally, U.S. Pat. No. 4,739,073 discloses certainsubstituted indoles, such as fluvastatin. Further, U.S. Pat. No.4,346,227 discloses ML-236B derivatives, such as pravastatin. Inaddition, EP 491,226 teaches certain pyridyldihydroxyheptenoic acids,such as rivastatin. Also, U.S. Pat. No. 4,647,576 discloses certain6-[2-(substituted-pyrrol-1-yl)-alkyl]-pyran-2-ones such as atorvastatin.Other HMG-CoA reductase inhibitors will be known to those skilled in theart. Examples of marketed products containing HMG-CoA reductaseinhibitors that can be used in combination with compounds of the presnetinvention include Baycol®, Lescol®, Lipitor®, Mevacor®, Pravachol® andZocor®.

[0490] Any HMG-CoA synthase inhibitor may be used as the second compoundin the combination therapy aspect of this invention. The term HMG-CoAsynthase inhibitor refers to a compound which inhibits the biosynthesisof hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A andacetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Suchinhibition may be determined readily by one of skill in the artaccording to standard assays (e.g., Methods of Enzymology, 35:155-160(1975); and Methods of Enzymology, 110: 19-26 (1985); and the referencescited therein). A variety of these compounds are described andreferenced below. U.S. Pat. No. 5,120,729 discloses certain beta-lactamderivatives. U.S. Pat. No. 5,064,856 discloses certain spiro-lactonederivatives prepared by culturing the microorganism MF5253. U.S. Pat.No. 4,847,271 discloses certain oxetane compounds such as 11-(3-hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undecadienoicacid derivatives. Other HMG-CoA synthase inhibitors will be known tothose skilled in the art.

[0491] Any compound that decreases HMG-CoA reductase gene expression maybe used as the second compound in the combination therapy aspect of thisinvention. These agents may be HMG-CoA reductase transcriptioninhibitors that block the transcription of DNA or translation inhibitorsthat prevent translation of mRNA coding for HMG-CoA reductase intoprotein. Such inhibitors may either affect transcription or translationdirectly, or may be biotransformed into compounds that have theaforementioned attributes by one or more enzymes in the cholesterolbiosynthetic cascade or may lead to the accumulation of an isoprenemetabolite that has the aforementioned activities. Such regulation isreadily determined by those skilled in the art according to standardassays (Methods of Enzymology, 110: 9-19 1985). Several such compoundsare described and referenced below however other inhibitors of HMG-CoAreductase gene expression will be known to those skilled in the art.U.S. Pat. No. 5,041,432 discloses certain 15-substituted lanosterolderivatives. Other oxygenated sterols that suppress the biosynthesis ofHMG-CoA reductase are discussed by E. I. Mercer (Prog. Lip. Res.,32:357-416 1993).

[0492] Any compound having activity as a CETP inhibitor can serve as thesecond compound in the combination therapy aspect of the instantinvention.

[0493] The term CETP inhibitor refers to compounds that inhibit thecholesteryl ester transfer protein (CETP) mediated transport of variouscholesteryl esters and triglycerides from HDL to LDL and VLDL. A varietyof these compounds are described and referenced below however other CETPinhibitors will be known to those skilled in the art. U.S. Pat. No.5,512,548 discloses certain polypeptide derivatives having activity asCETP inhibitors, while certain CETP-inhibitory rosenonolactonederivatives and phosphate-containing analogs of cholesteryl ester aredisclosed in J. Antibiot., 49(8): 815-816 (1996), and Bioorg. Med. Chem.Lett.; 6:1951-1954 (1996), respectively. Other CETP inhibitors that canbe used in combination with compounds of the present invention aredisclosed in WO 99/20302, EP 796846, EP818197, EP 818448, WO 99/14204,WO 99/41237, WO 95/04755, WO 96/15141, WO 96/05227, DE 19704244,DE19741051, DE 19741399, DE 19704243, DE 19709125, DE 19627430, DE19832159, DE 19741400, JP 11049743, and JP 09059155. Preferred CETPinhibitors that can be used in combination with the compounds of thepresent invention include

[0494] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[0495] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[0496] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 2-hydroxy-ethyl ester;

[0497] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[0498] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[0499] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid propyl ester; and

[0500] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester,

[0501] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid isopropyl ester;

[0502] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[0503] [2S,4S]2-cyclopropyl4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[0504] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid tert-butyl ester;

[0505] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[0506] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[0507] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[0508] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[0509] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 2-hydroxy-ethyl ester;

[0510] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[0511] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[0512] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; and

[0513] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid propyl ester, andpharmaceutically acceptable salts and prodrugs thereof and salts of theprodrugs.

[0514] Any ACAT inhibitor can serve as the second compound in thecombination therapy aspect of this invention. The term ACAT inhibitorrefers to compounds that inhibit the intracellular esterification ofdietary cholesterol by the enzyme acyl CoA: cholesterol acyltransferase.Such inhibition may be determined readily by one of skill in the artaccording to standard assays, such as the method of Heider et al.described in Journal of Lipid Research., 24:1127 (1983). A variety ofthese compounds are described and referenced below; however, other ACATinhibitors will be known to those skilled in the art. U.S. Pat. No.5,510,379 discloses certain carboxysulfonates, while WO 96/26948 and WO96/10559 both disclose urea derivatives having ACAT inhibitory activity.

[0515] Any compound having activity as a squalene synthetase inhibitorcan serve as an additional compound in the combination therapy aspect ofthe instant invention. The term squalene synthetase inhibitor refers tocompounds that inhibit the condensation of two molecules offarnesylpyrophosphate to form squalene, a reaction that is catalyzed bythe enzyme squalene synthetase. Such inhibition is readily determined bythose skilled in the art according to standard methodology (Methods ofEnzymology, 15:393-454 (1969); and Methods of Enzymology, 110: 359-373(1985); and references cited therein). A summary of squalene synthetaseinhibitors has been complied in Curr. Op.Ther. Patents, 861-4, (1993).European patentapplication publication Number 0 567 026 Al disclosescertain 4,1-benzoxazepine derivatives as squalene synthetase inhibitorsand their use in the treatment of hypercholesterolemia and asfungicides. European patent application publication Number 0 645 378 A1discloses certain seven- or eight-membered heterocycles as squalenesynthetase inhibitors and their use in the treatment and preventionhypercholesterolemia and fungal infections. European patent applicationpublication Number 0 645 377 A1 discloses certain benzoxazepinederivatives as squalene synthetase inhibitors useful for the treatmentof hypercholesterolemia or coronary sclerosis. European patentapplication publication Number 0 611 749 A1 discloses certainsubstituted amic acid derivatives useful for the treatment ofarteriosclerosis. European patent application publication Number 0 705607 A2 discloses certain condensed seven- or eight-membered heterocycliccompounds useful as antihypertriglyceridemic agents. PCT publication WO96/09827 discloses certain combinations of cholesterol absorptioninhibitors and cholesterol biosynthesis inhibitors includingbenzoxazepine derivatives and benzothiazepine derivatives. Europeanpatent application publication Number 0 701 725 A1 discloses a processfor preparing certain optically-active compounds, includingbenzoxazepine derivatives, having plasma cholesterol and triglyceridelowering activities. Other compounds that are marketed forhyperlipidemia, including hypercholesterolemia and which are intended tohelp prevent or treat atherosclerosis include bile acid sequestrants,such as Colestid®, LoCholest® and Questran®; and fibric acidderivatives, such as Atromid®, Lopid® and Tricor®. These compounds canalso be used in combination with a compound of the present invention.

[0516] It is also contemplated that the compounds of the presentinvention be administered with a lipase inhibitor and/or a glucosidaseinhibitor, which are typically used in the treatment of conditionsresulting from the presence of excess triglycerides, free fatty acids,cholesterol, cholesterol esters or glucose including, inter alia,obesity, hyperlipidemia, hyperlipoproteinemia, Syndrome X, and the like.

[0517] In a combination with a compound of the present invention, anylipase inhibitor or glucosidase inhibitor may be employed. Preferredlipase inhibitors comprise gastric or pancreatic lipase inhibitors suchas orlistat. Preferred glucosidase inhibitors comprise amylaseinhibitors.

[0518] A lipase inhibitor is a compound that inhibits the metaboliccleavage of dietary triglycerides into free fatty acids andmonoglycerides. Under normal physiological conditions, lipolysis occursvia a two-step process that involves acylation of an activated serinemoiety of the lipase enzyme. This leads to the production of a fattyacid-lipase hemiacetal intermediate, which is then cleaved to release adiglyceride. Following further deacylation, the lipase-fatty acidintermediate is cleaved, resulting in free lipase, a monoglyceride and afatty acid. The resultant free fatty acids and monoglycerides areincorporated into bile acid-phospholipid micelles, which aresubsequently absorbed at the level of the brush border of the smallintestine. The micelles eventually enter the peripheral circulation aschylomicrQns. Accordingly, compounds, including lipase inhibitors thatselectively limit or inhibit the absorption of ingested fat precursorsare useful in the treatment of conditions including obesity,hyperlipidemia, hyperlipoproteinemia, Syndrome X, and the like.

[0519] Pancreatic lipase mediates the metabolic cleavage of fatty acidsfrom triglycerides at the 1- and 3-carbon positions. The primary site ofthe metabolism of ingested fats is in the duodenum and proximal jejunumby pancreatic lipase, which is usually secreted in vast excess of theamounts necessary for the breakdown of fats in the upper smallintestine. Because pancreatic lipase is the primary enzyme required forthe absorption of dietary triglycerides, inhibitors have utility in thetreatment of obesity and the other related conditions.

[0520] Gastric lipase is an immunologically distinct lipase that isresponsible for approximately 10 to 40% of the digestion of dietaryfats. Gastric lipase is secreted in response to mechanical stimulation,ingestion of food, the presence of a fatty meal or by sympatheticagents. Gastric lipolysis of ingested fats is of physiologicalimportance in the provision of fatty acids needed to trigger pancreaticlipase activity in the intestine and is also of importance for fatabsorption in a variety of physiological and pathological conditionsassociated with pancreatic insufficiency. See, for example, C. K.Abrams, et al., Gastroenterology, 92, 125 (1987).

[0521] A variety of lipase inhibitors are known to one of ordinary skillin the art. However, in the practice of the methods, pharmaceuticalcompositions and kits of the instant invention, generally preferredlipase inhibitors are those inhibitors that are selected from the groupconsisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386,WAY-121898, Bay-N-3176, valilactone, esterastin, ebelactone A,ebelactone B and RHC 80267.

[0522] The pancreatic lipase inhibitors lipstatin, 2S, 3S, 5S,10Z)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-7,10-hexadecanoic acid lactone, and tetrahydrolipstatin (orlistat), 2S,3S,5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoicacid lactone, and the variously substituted N-formyllecunie derivativesand stereoisomers thereof, are disclosed in U.S. Pat. No. 4,598,089.

[0523] The pancreatic lipase inhibitor FL-386,1-[4-(2-methylpropyl)cyclohexyl]-2-[(phenylsulfonyl) oxy]-ethanone, andthe variously substituted sulfonate derivatives related thereto, aredisclosed in U.S. Pat. No. 4,452,813.

[0524] The pancreatic lipase inhibitor WAY-1 21898,4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and the variouscarbamate esters and pharmaceutically acceptable salts related thereto,are disclosed in U.S. Pat. Nos. 5,512,565; 5,391,571 and 5,602,151.

[0525] The lipase inhibitor Bay-N-3176,N-3-trifluoromethylphenyl-N′-3-chloro-4′-trifluoromethylphenylurea, andthe various urea derivatives related thereto, are disclosed in U.S. Pat.No. 4,405,644.

[0526] The pancreatic lipase inhibitor valilactone, and a process forthe preparation thereof by the microbial cultivation of Actinomycetesstrain MG147—CF2, are disclosed in Kitahara, et al., J. Antibiotics, 40(11), 1647-1650 (1987).

[0527] The lipase inhibitor esteracin, and certain processes for thepreparation thereof by the microbial cultivation of Streptomyces strainATCC 31336, are disclosed in U.S. Pat. Nos. 4,189,438 and 4,242,453.

[0528] The pancreatic lipase inhibitors ebelactone A and ebelactone B,and a process for the preparation thereof by the microbial cultivationof Actinomycetes strain MG7-Gl, are disclosed in Umezawa, et al., JAntibiotics, 33, 1594-1596 (1980). The use of ebelactones A and B in thesuppression of monoglyceride formation is disclosed in Japanese Kokai08-143457, published Jun. 4, 1996.

[0529] The lipase inhibitor RHC 80267,cyclo-O,O′-[(1,6-hexanediyl)-bis-(iminocarbonyl) ]dioxime, and thevarious bis(iminocarbonyl)dioximes related thereto may be prepared asdescribed in Petersen et al., Liebig's Annalen, 562, 205-229 (1949). Theability of RHC 80267 to inhibit the activity of myocardial lipoproteinlipase is disclosed in Carroll et al., Lipids, 27, pp. 305-307 (1992)and Chuang et al., J. Mol. Cell Cardiol., 22, 1009-1016 (1990).

[0530] A glucosidase inhibitor inhibits the enzymatic hydrolysis ofcomplex carbohydrates by glycoside hydrolases, for example amylase ormaltase, into bioavailable simple sugars, for example, glucose. Therapid metabolic action of glucosidases, particularly following theintake of high levels of carbohydrates, results in a state of alimentaryhyperglycemia which, in adipose or diabetic subjects, leads to enhancedsecretion of insulin, increased fat synthesis and a reduction in fatdegradation. Following such hyperglycemias, hypoglycemia frequentlyoccurs, due to the augmented levels of insulin present. Additionally, itis known that both hypoglycemias and chyme remaining in the stomachpromotes the production of gastric juice which initiates or favors thedevelopment of gastritis or duodenal ulcers. Accordingly, glucosidaseinhibitors are known to have utility in accelerating the passage ofcarbohydrates through the stomach and inhibiting the absorption ofglucose from the intestine. Furthermore, the conversion of carbohydratesinto lipids of the fatty tissue and the subsequent incorporation ofalimentary fat into fatty tissue deposits is accordingly reduced ordelayed, with the concomitant benefit of reducing or preventing thedeleterious abnormalities resulting therefrom.

[0531] In combination with a compound of the present invention, anyglucosidase inhibitor may be employed, however, a generally preferredglucosidase inhibitor comprises an amylase inhibitor. An amylaseinhibitor is a glucosidase inhibitor that inhibits the enzymaticdegradation of starch or glycogen into maltose. The inhibition of suchenzymatic degradation is beneficial in reducing amounts of bioavailablesugars, including glucose and maltose, and the concomitant deleteriousconditions resulting therefrom.

[0532] A variety of glucosidase and amylase inhibitors are known to oneof ordinary skill in the art. However, in the practice of the methodsand pharmaceutical compositions of the instant invention, generallypreferred glucosidase inhibitors are those inhibitors that are selectedfrom the group consisting of acarbose, adiposine, voglibose, miglitol,emiglitate, MDL-25637, camiglibose, tendamistate, Al-3688, trestatin,pradimicin-Q and salbostatin.

[0533] The glucosidase inhibitor acarbose, O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1 -yl]amino]-α-glucopyranosyl-(1 - - - >4)—O—α-D-glucopyranosyl-(1 - - ->4)-D-glucose, the various amino sugar derivatives related thereto and aprocess for the preparation thereof by the microbial cultivation ofActinoplanes strains SE 50 (CBS 961.70), SB 18 (CBS 957.70), SE 82 (CBS615.71), SE 50/13 (614.71) and SE 50/110 (674.73) are disclosed in U.S.Pat. Nos. 4,062,950 and 4,174,439 respectively.

[0534] The glucosidase inhibitor adiposine, consisting of adiposineforms 1 and 2, is disclosed in U.S. Pat. No. 4,254,256. Additionally, aprocess for the preparation and purification of adiposine is disclosedin Namiki et al., J. Antiobiotics, 35, 1234-1236 (1982).

[0535] The glucosidase inhibitor voglibose,3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2—C-(hydroxymethyl)-D-epi-inositol, and the variousN-substituted pseudo-aminosugars related thereto, are disclosed in U.S.Pat. No. 4,701,559.

[0536] The glucosidase inhibitor miglitol,(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol, and the various 3,4,5-trihydroxypiperidines relatedthereto, are disclosed in U.S. Pat. No. 4,639,436.

[0537] The glucosidase inhibitor emiglitate, ethylp-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]ethoxy]-benzoate, the various derivatives related thereto andpharmaceutically acceptable acid addition salts thereof, are disclosedin U.S. Pat. No. 5,192,772.

[0538] The glucosidase inhibitor MDL-25637,2,6-dideoxy-7—O—β-D-glucopyrano-syl-2,6-imino-D-glycero-L-gluco-heptitol, the various homodisaccharidesrelated thereto and the pharmaceutically acceptable acid addition saltsthereof, are disclosed in U.S. Pat. No. 4,634,765.

[0539] The glucosidase inhibitor camiglibose, methyl6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]-α-D-glucopyranosidesesquihydrate, the deoxy-nojirimycin derivatives related thereto, thevarious pharmaceutically acceptable salts thereof and synthetic methodsfor the preparation thereof, are disclosed in U.S. Pat. Nos. 5,157,116and 5,504,078.

[0540] The amylase inhibitor tendamistat, the various cyclic peptidesrelated thereto and processes for the preparation thereof by themicrobial cultivation of Streptomyces tendae strains 4158 or HAG 1226,are disclosed in U.S. Pat. No. 4,451,455.

[0541] The amylase inhibitor Al-3688, the various cyclic polypeptidesrelated thereto, and a process for the preparation thereof by themicrobial cultivation of Streptomyces aureofaciens strain FH 1656, aredisclosed in U.S. Pat. No. 4,623,714.

[0542] The amylase inhibitor trestatin, consisting of a mixture oftrestatin A, trestatin B and trestatin C, the varioustrehalose-containing aminosugars related thereto and a process for thepreparation thereof by the microbial cultivation of Streptomycesdimorphogenes strains NR-320-OM7HB and NR-320-OM7HBS, are disclosed inU.S. Pat. No. 4,273,765.

[0543] The glucosidase inhibitor pradimicin-Q and a process for thepreparation thereof by the microbial cultivation of Actinomaduraverrucospora strains R 103-3 or A10102, are disclosed in U.S. Pat. Nos.5,091,418 and 5,217,877 respectively.

[0544] The glycosidase inhibitor salbostatin, the variouspseudosaccharides related thereto, the various pharmaceuticallyacceptable salts thereof and a process for the preparation thereof bythe microbial cultivation of Streptomyces albus strain ATCC 21838, aredisclosed in U.S. Pat. No. 5,091,524.

[0545] Preferred lipase inhibitors comprise compounds selected from thegroup consisting of lipstatin, tetrahydrolipstatin, FL-386, WAY-121898,Bay-n-3176, valilactone, esteracin, ebelactone A, ebelactone B, RHC80267, stereoisomers thereof, and pharmaceutically acceptable salts ofsaid compounds and stereoisomers. The compound tetrahydrolipstatin isespecially preferred.

[0546] Preferred glucosidase inhibitors comprise compounds selected fromthe group consisting of acarbose, adiposine, voglibose, miglitol,emiglitate, MDL-25637, camiglibose, pradimicin-Q, and salbostatin. Anespecially preferred glucosidase inhibitor is acarbose. Especiallypreferred glucosidase inhibitors further comprise amylase inhibitorsthat are selected from the group consisting of tendamistate, Al-3688 andtrestatin.

[0547] In addition, it is contemplated that the estrogenagonist/antagonist can be used in combination with MTP inhibitors and/orapo B secretion inhibitors.

[0548] A variety of apo B secretion/MTP inhibitors are known to one ofordinary skill in the art. Although any apo B secretion/MTP inhibitormay be used in the practice of the methods and pharmaceuticalcompositions of the instant invention, generally preferred apo Bsecretion/MTP inhibitors include those compounds that are disclosed in,for example, European Patent Application Publication Numbers EP 643057,EP 719763, EP 753517, EP 764647, EP 765878, EP 779276, EP 779279, EP799828, EP 799829, EP 802186, EP 802188, EP 802192, and EP 802197; PCTApplication Publication Numbers WO 96/13499, WO 96/33193, WO 96/40640,WO 97/26240, WO 97/43255, WO 97/43257, WO 98/16526 and WO 98/23593; andU.S. Pat. Nos. 5,595,872; 5,646,162; 5,684,014; 5,712,279; 5,739,135 and5,789,197.

[0549] Especially preferred apo-B secretion/MTP inhibitors are thosebiphenyl-2-carboxylic acid-tetrahydroisoquinolin-6-yl amide derivativesdisclosed in PCT Application Publication Numbers WO 96/40640 and WO98/23593. Especially preferred apo B secretion/MTP inhibitors disclosedin PCT Application Publication Numbers WO 96/40640 and WO 98/23593, anduseful in the methods and pharmaceutical compositions of the presentinvention, are 4′-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquin-6-yl]-amide and4′-trifluoromethyl-biphenyl-2-carboxylicacid-[2-(acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide.

[0550] Another especially preferred class of apo B secretion/MTPinhibitors is disclosed in U.S. Pat. Nos. 5,595,872; 5,721,279;5,739,135 and 5,789,197.

[0551] Especially preferred apo B secretion/MTP inhibitors disclosed inU.S. Pat. Nos. 5,595,872; 5,721,279; 5,739,135 and 5,789,197 and usefulin the methods and pharmaceutical compositions of the present invention,are 9-(4-{4-[4′ trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-butyl-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amideand 9-{4-[4-(2-benzothiazol-2-yl-benzoylamino)-piperidin-1-yl]-butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.

[0552] Another class of especially preferred apo B secretion/MTPinhibitors is disclosed in PCT Application Publication Number WO98/16526.

[0553] Especially preferred apo B secretion/MTP inhibitors disclosed inPCT Application Publication Number WO 98/16526, and useful in themethods and pharmaceutical compositions of the present invention, are[11a-R]-8-[(4-cyanophenyl)methoxy]-2-cyclopentyl-7-(prop-2-enyl)-2,3,11,11a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione and[11a-R]-cyclopentyl-7-(prop-2-enyl)-8-[(pyridin-2-yl) methoxy]-2,3,11,11a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione.

[0554] Another especially preferred class of apo B secretion/MTPinhibitors is disclosed in U.S. Pat. No. 5,684,014.

[0555] An especially preferred apo B secretion/MTP inhibitor disclosedin U.S. Pat. No. 5,684,014, and useful in the methods and pharmaceuticalcompositions of the present invention, is2-cyclopentyl-2-[4-(2,4-dimethyl-pyrido[2,3-b]indol-9-ylmethyl)-phenyl]—N—(2-hydroxy-1-phenyl-ethyl)-acetamide.

[0556] Yet another class of especially preferred apo B secretion/MTPinhibitors is disclosed in U.S. Pat. No. 5,646,162.

[0557] An especially preferred apo B secretion/MTP inhibitor disclosedin U.S. Pat. Number 5,646,162 and useful in the methods andpharmaceutical compositions of the present invention, is2-cyclopentyl-N-(2-hydroxy-1-phenylethyl)-2-[4-(quinolin-2-ylmethoxy)-phenyl]-acetamide.

[0558] Compounds that are used to treat Raynaud's phenomenon includenifedipine and phenoxybenzamine. These compounds and others used totreat Raynaud's disease can be used in combination with estrogenagonists/antagonists.

[0559] The estrogen agonists/antagonists of the present invention canalso be administered in combination with antihypertensives. Examples ofclasses of compounds that can be used to treat hypertension includecalcium blockers, ACE inhibitors, diuretics, angiotensin II receptorblockers, β-blockers, and α-adrenergic blockers. In addition,combinations of compounds in the above-recited classes have been used totreat hypertension. Some examples of specific compounds that can be usedin combination with an estrogen agonsit/antagonist include quinapril;amlodipine, including the besylate salt; nifedipine; doxazosin,including the mesylate salt; and prazosin, including the hydrochloridesalt.

[0560] In the combination aspect of the methods and kits of the presentinvention, the estrogen agonist/antagonist and any additional compoundscan be administered in the same dosage form or in separate dosage forms.The dosage forms can be the same (e.g., both tablets) or different.Likewise, the compounds can be administered at the same time or atdifferent times. All variations are intended to be included in thepresent methods and kits.

[0561] The examples presented below are intended to exemplify particularembodiments of the invention and are not intended to limit thespecification, including the claims, in any manner.

[0562] All documents cited herein, including patents and patentapplications, are hereby incorporated by reference.

EXAMPLE

[0563] Brachial Artery Reactivity—Clinical Trial

Brachial Artery Imaging and Analysis

[0564] Introduction

[0565] One of the primary outcomes for this study will be the change inendothelial-dependent vasodilator capacity in the brachial arteryfollowing 8 weeks of treatment with(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol, conjugatedequine estrogen or placebo. The vasodilator stimulus used will be anincrease in brachial artery flow caused by ischemic hyperemia in thedistal limb. The changes in diameter of the brachial artery will beimaged using high resolution 2-D ultrasound with the measurement ofchange in diameter being based on image processing techniquesspecifically designed to measure diameter of the brachial artery usingautomated boundary detection algorithms. Through the use of standardizedprotocols for subject preparation, image acquisition and image analysis,accurate and precise measurement of brachial artery diameter and wallthickness have been developed, validated and employed in numerousclinical studies.

[0566] Participants are allowed to rest in the supine position for 10minutes in a quiet room. A blood pressure cuff is placed on the rightforearm just below the antecubital fossa and the arm is supported withsand bags to allow inflation and deflation of the blood pressure cuffwithin movement of the arm. The blood pressure and heart rate aremeasured in the left arm using an automated sphygmomanometer. Once acomfortable and secure position has been established and the bloodpressure is determined, images of the brachial artery at baseline areobtained (see section entitled “Image Acquisition”). After baselineimaging, the blood pressure cuff is rapidly inflated to 30 mm Hg greaterthan the systolic blood pressure for 5 minutes. The brachial artery isimaged again starting 30 seconds prior to cuff release and continuingfor a total of 3 minutes following cuff release.

[0567] Image Acquisition

[0568] The right brachial artery is examined approximately 7 cm proximalto the bend of the elbow using a high resolution ultrasound system. Abrief doppler signal is recorded in the vessel to confirmidentification. Once the near and far wall boundaries are visualizedwith careful transducer movements, the transducer is maintained at thislocation throughout the examination. Careful observation of surroundingtissues provide internal landmarks to confirm that this is accomplished.Baseline images are then recorded for approximately 2 minutes on a videorecorder. During the 5-minute interval during which the right bloodpressure cuff is inflated to 30 mmHg above systolic pressure, thesonographer alternately views the B-mode image and the doppler signal toconfirm that a high quality image is being maintained and that asignificant modification of blood flow is being achieved in the vessel.During the final 30 seconds prior to rapid cuff deflation, high qualityB-mode images are recorded. Immediately after cuff release, dopplersignals are recorded for 10-15 seconds to observe the peak flow aftercuff release, after which high quality B-mode images are continuouslyrecorded for 3 minutes.

[0569] Image Analysis

[0570] The videotape is completely reviewed by the image analysistechnicians prior to analysis. After identifying the portion of the tapedemonstrating the brachial artery at baseline, 30 frames are digitizedwith a frame grabber into 512×512 ×8 bit grey scales and stored on theimage analysis computer. Using a semi-automated boundary detectionalgorithm, the medial-advenitial boundary on the near and far wall ofthe brachial artery is located over an arterial segment 2.0-2.5 cm inlength. If a boundary point is obviously displaced from the truelocation of the medial-adventitial boundary, then the image analysistechnician will manually edit the boundary point in question. However,every effort is made to minimize the editing used. The average diameterof the artery is automatically calculated and the mean diameter from the3-D baseline frames is used to determine the baseline diameter. Theexact same procedure is repeated to determine the diameter of the arteryjust prior to cuff release. Similar methods are used to determine themaximum diameter that occurs during the 3 minutes immediately followingcuff release. Time from cuff release to point of maximum dilation willalso be recorded.

[0571] Primary and Secondary Outcome Measures

[0572] The primary outcome measure is relative change in mean arterialdiameter calculated as follows:$\frac{\max \quad {diameter}}{{baseline}\quad {diameter}} \times 100.$

[0573] Time to maximum dilation and percent change from end of cuffocclusion to maximum dilation will also be determined.

What is claimed is:
 1. A method of preventing myocardial infarction orstroke; maintaining or improving vascular reactivity; or treating acuteor chronic renal failure, peripheral arterial occlusive disease,coronary artery disease, or Raynaud's phenomenon, the method comprisingadministering to a patient at risk of having a myocardial infarction ora stroke; in need of maintenance or improvement of vascular reactivity;or having acute or chronic renal failure, peripheral arterial occlusivedisease, coronary artery disease, or Raynaud's phenomenon, atherapeutically effective amount of an estrogen agonist/antagonist. 2.The method of claim 1 wherein the estrogen agonist/antagonist is acompound of formula (I):

wherein: A is selected from CH₂ and NR; B, D and E are independentlyselected from CH and N; Y is (f) C₁—C₄ alkylthio; (g) C₁—C₄alkylsulfinyl; (h) C₁—C₄ alkylsulfonyl; (i) hydroxy (C₁—C₄)alkyl; (j)aryl (C₁—C₄)alky); (k) —CO₂H; (l) —CN; (m) —CONHOR; (n) —SO₂NHR; (o)—NH₂; (p) C₁—C₄ alkylamino; (q) C₁—C₄ dialkylamino; (r) —NHSO₂R; (s) 13NO₂; (t) -aryl; or (u) —OH; R⁵ and R⁶ are independently C₁—C₈ alkyl ortogether form a C₃—C₁₀ carbocyclic ring; R⁷ and R⁸ are independently (a)phenyl; (b) a C₃—C₁₀ carbocyclic ring, saturated or unsaturated; (c) aC₃—C₁₀ heterocyclic ring containing up to two heteroatoms, selected from—O—, —N— and —S—; (d) H; (e) C₁—C₆ alkyl; or (f) form a 3 to 8 memberednitrogen containing ring with R⁵ or R⁶; R⁷ and R⁸ in either linear orring form may optionally be substituted with up to three substituentsindependently selected from C₁—C₆ alkyl, halogen, alkoxy, hydroxy andcarboxy; a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring; e is 0, 1 or 2; m is 1, 2 or 3; n is 0, 1 or 2; p is 0, 1, 2or 3;q is 0, 1, 2or 3; or an optical or geometric isomer thereof; or apharmaceutically acceptable salt, N-oxide, ester, quaternary ammoniumsalt or prodrug thereof.
 3. The method of claim 1 wherein the estrogenagonist/antagonist is a compound of formula (IA)

R ⁴is H, OH, F, or Cl; and B and E are independently selected from CHand N or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrugthereof.
 4. The method of claim 3 wherein the estrogenagonist/antagonist is(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl ]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomerthereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternaryammonium salt, or a prodrug thereof.
 5. The method of claim 4 whereinthe estrogen agonist/antagonist is in the form of a D-tartrate salt. 6.The method of claim 1 wherein said estrogen agonist/antagonist is acompound selected from the formulas V or VI:

wherein: R_(1B) is selected from H, OH, —O—C(O)—C₁—C₁₂ alkyl (straightchain or branched), —O—C₁—C₁₂ alkyl (straight chain or branched orcyclic), or halogens or C₁—C₄ halogenated ethers; R_(2B), R_(3B),R_(4B). R_(5B), and R_(6B) are independently selected from H, OH,—O—C(O)—C₁—C₁₂ (straight chain or branched), —O—C₁—C₁₂ (straight chainor branched or cyclic), halogens, or C₁—C₄ halogenated ethers, cyano,C₁—C₆ alkyl (straight chain or branched), or trifluoromethyl; X_(A) isselected from H, C₁—C₈ alkyl, cyano, nitro, trifluoromethyl, andhalogen; s is 2 or 3; Y_(A) is the moiety:

wherein: a) R_(7B) and R_(8B) are independently selected from the groupof H, C₁—C₆ alkyl, or phenyl optionally substituted by CN, C₁—C₆ alkyl(straight chain or branched), C₁—C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; or b) R_(7B) and R_(8B) are concatenatedto form a five-membered saturated heterocycle containing one nitrogenheteroatom, the heterocycle being optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl,C₁—C4 alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁—C₄)alkyl; or c)R_(7B) and R_(8B) are concatenated to form a six-membered saturatedheterocycle containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁—C₄ alkyl,trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄alkylthio, C₁—C₄alkylsulfinyl, C₁—C₄ alkylsulfonyl, hydroxy(C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or d) R_(7B) and R_(8B) areconcatenated to form a seven-membered saturated heterocycle containingone nitrogen heteroatom, the heterocycle being optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (CI—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄ alkyl)₂, —NHSO₂ R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁—C₄)alkyl; or (a)phenyl, optionally substituted with 1-3 substituents independentlyselected from R⁴; (b) naphthyl, optionally substituted with 1-3substituents independently selected from R⁴; (c) C₃—C₈ cycloalkyl,optionally substituted with 1-2 substituents independently selected fromR⁴; (d) C₃—C₈ cycloalkenyl, optionally substituted with 1-2 substituentsindependently selected from R⁴; (e) a five membered heterocyclecontaining up to two heteroatoms selected from the group consisting of—O—, —NR²- and —S(O)_(n)-, optionally substituted with 1-3 substituentsindependently selected from R⁴; (f) a six membered heterocyclecontaining up to two heteroatoms selected from the group consisting of—O—, —NR²- and —S(O)_(n)- optionally substituted with 1-3 substituentsindependently selected from R⁴; or (g) a bicyclic ring system consistingof a five or six membered heterocyclic ring fused to a phenyl ring, saidheterocyclic ring containing up to two heteroatoms selected from thegroup consisting of —O—, —NR²- and —S(O)_(n)-, optionally substitutedwith 1-3 substituents independently selected from R⁴; Z¹ is (a)—(CH₂)_(p) W(CH₂)_(q)-; (b) —O(CH₂)_(p) CR⁵R⁶-; (c)—O(CH₂)_(p)W(CH₂)_(q)-; (d) —OCHR²CHR³; or (e) —SCHR²CHR³—; G is (a)—NR⁷R⁸;

wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or —CH₂—;optionally fused on adjacent carbon atoms with one or two phenyl ringsand, optionally independently substituted on carbon with one to threesubstituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or (c) a bicyclicamine containing five to twelve carbon atoms, either bridged or fusedand optionally substituted with 1-3 substituents independently selectedfrom R⁴; or Z¹ and G in combination may be

W is (a) —CH₂—; (b) —CH=CH—; (c) —O—; (d) —NR²—; (e) —S(O)_(n)-;

(g) —CR²(OH)—; (h) —CONR²; (i) —NR²CO—;

(k) —C≡C—; R is hydrogen or C₁—C₆ alkyl; R² and R³ are independently (a)hydrogen; or (b) C₁—C₄ alkyl; R⁴ is (a) hydrogen; (b) halogen; (c) C₁—C₆alkyl; (d) C₁—C₄ alkoxy; (e) C₁—C₄ acyloxy; e) R_(7B) and R_(8B) areconcatenated to form an eight-membered saturated heterocycle containingone nitrogen heteroatom, the heterocycle being optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁—C₄)alkyl; or f)R_(7B) and R_(8B) are concatenated to form a saturated bicyclicheterocycle containing from 6-12 carbon atoms either bridged or fusedand containing one nitrogen heteroatom, the heterocycle being optionallysubstituted with 1-3 substituents independently selected from the groupconsisting of hydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl,C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁—C₄alkylsulfinyl, C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂ H, —CN,—CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B),—NHCOR_(1B), —NO₂, or phenyl optionally substituted with 1-3 (C₁—C₄)alkyl; or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.
 7. The method of claim 1 wherein the estrogenagonist/antagonist is the compound TSE-424 of formula Va below:

or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.
 8. The method of claim 1 wherein the estrogenagonist/antagonist is EM-652 of formula III below or is EM-800 offormula IV below:

or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.
 9. The method of claim 1 wherein a second compound that isuseful to prevent myocardial infarction or stroke; maintain or improvingvascular reactivity; or treat acute or chronic renal failure, peripheralarterial occlusive disease, coronary artery disease, or Raynaud'sphenomenon, is administered to the patient.
 10. A method of lowering theplasma concentration of Lp(a), the method comprising administering to apatient in need of plasma Lp(a) lowering a therapeutically effectiveamount of an estr ogen agonist/antagonist.
 11. The method of claim 10wherein the estrogen agonist/antagonist is a compound of formula (I):

wherein: A is selected from CH₂ and NR; B, D and E are independentlyselected from CH and N; Y is (a) phenyl, optonally substtuted with 1-3substituents independently selected from R⁴; (b) naphthyl, optionallysubstituted with 1-3 substituents independently selected from R⁴; (c)C₃—C₈ cycloalkyl, optionally substituted with 1-2 substituentsindependently selected from R⁴; (d) C₃—C₈ cycloalkenyl, optionallysubstituted with 1-2 substituents independently selected from R⁴; (e) afive membered heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NR ²— and —S(O)_(n)-, optionallysubstituted with 1-3 substituents independently selected from R⁴; (f) asix membered heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NR²— and —S(O)_(n)- optionally substitutedwith 1-3 substituents independently selected from R⁴; or (g) a bicyclicring system consisting of a five or six membered heterocyclic ring fusedto a phenyl ring, said heterocyclic ring containing up to twoheteroatoms selected from the group consisting of —O—, —NR²— and—S(O)_(n)-, optionally substituted with 1-3 substituents independentlyselected from R⁴; Z¹ is (a) —(CH₂)_(p) W(CH₂)_(q)-; (b) —O(CH₂)_(p)CR⁵R⁶-; (c) —O(CH₂)_(p)W(CH₂)_(q)-; (d) —OCHR²CHR³-; or (e) —SCHR²CHR³-;G is (a) —NR⁷R⁸;

wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or —CH₂—;optionally fused on adjacent carbon atoms with one or two phenyl ringsand, optionally independently substituted on carbon with one to threesubstituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or (c) a bicyclicamine containing five to twelve carbon atoms, either bridged or fusedand optionally substituted with 1-3 substituents independently selectedfrom R⁴; or Z¹ and G in combination may be

W is (a) —CH₂—; (b) —CH═CH—; (c) —O—; (d) —NR²—; (e) —S(O)_(n)-;

(g) —CR²(OH)—; (h) —CONR²—; (i) —NR²CO—;

(k) —C≡C—; R is hydrogen or C₁—C₆ alkyl; R² and R³ are independently (a)hydrogen; or (b) C₁—C₄ alkyl; R⁴ is (a) hydrogen; (b) halogen; (c) C₁—C₆alkyl; (d) C₁—C₄ alkoxy; (e) C₁—C₄ acyloxy; (f) C₁—C₄ alkylthio; (g)C₁—C₄ alkylsulfinyl; (h) C₁—C₄ alkylsulfonyl; (i) hydroxy (C₁—C₄)alkyl;(j) aryl (C₁—C₄)alkyl; (k) —CO₂H; (l) —CN; (m) —CONHOR; (n) —SO₂NHR; (o)—NH₂; (p) C₁—C₄ alkylamino; (q) C₁—C₄ dialkylamino; (r) —NHSO₂R; (p)C₁—C₄ alkylamino; (q) C₁—C₄ dialkylamino; (r) —NHSO₂R; (s) —NO₂; (t)-aryl; or (u) —OH; R⁵ and R⁶ are independently C₁—C₈ alkyl or togetherform a C₃—C₁₀ carbocyclic ring; R⁷ and R⁸ are independently (a) phenyl;(b) a C₃—C₁₀ carbocyclic ring, saturated or unsaturated; (c) a C₃—C₁₀heterocyclic ring containing up to two heteroatoms, selected from —O—,—N— and —S—; (d) H; (e) C₁—C₆ alkyl; or (f) form a 3 to 8 memberednitrogen containing ring with R⁵ or R⁶; R⁷ and R⁸ in either linear orring form may optionally be substituted with up to three substituentsindependently selected from C₁—C₆ alkyl, halogen, alkoxy, hydroxy andcarboxy; a ring formed by R⁷ and R⁸ may be optionally fused to a phenylring; e is 0, 1 or 2; m is 1, 2 or 3; n is 0, 1 or 2; p is 0, 1, 2 or 3;q is 0, 1, 2 or 3; or an optical or geometric isomer thereof; or apharmaceutically acceptable salt, N-oxide, ester, quaternary ammoniumsalt or prodrug thereof.
 12. The method of claim 10 wherein the estrogenagonist/antagonist is a compound of formula (IA):

R⁴ is H, OH, F, or Cl; and B and E are independently selected from CHand N or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrugthereof.
 13. The method of claim 12 wherein the estrogenagonist/antagonist is (-)-cis-6- phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical orgeometric isomer thereof; a pharmaceutically acceptable salt, N-oxide,ester, quaternary ammonium salt, or a prodrug thereof.
 14. The method ofclaim 13 wherein the estrogen agonist/antagonist is in the form of aD-tartrate salt.
 15. The method of claim 10 wherein said estrogenagonist/antagonist is a compound selected from the formulas V or VI:

wherein: R_(1B) is selected from H, OH, —O—C(O)—C₁—C₁₂ alkyl (straightchain or branched), —O—C₁—C₁₂ alkyl (straight chain or branched orcyclic), or halogens or C —C₄ halogenated ethers; R_(2B), R_(3B),R_(4B), R_(5B), and R_(6B) are independently selected from H, OH,—O—C(O)—C₁—C₁₂ (straight chain or branched), —O—C₁—C₁₂ (straight chainor branched or cyclic), halogens, or C₁—C₄ halogenated ethers, cyano,C₁—C₆ alkyl (straight chain or branched), or trifluoromethyl; X_(A) isselected from H, C₁—C₆ alkyl, cyano, nitro, trifluoromethyl, andhalogen; s is 2 or 3; Y_(A) is the moiety:

wherein: a) R_(7B) and R_(8B) are independently selected from the groupof H, C₁—C₆ alkyl, or phenyl optionally substituted by CN, C₁—C₆ alkyl(straight chain or branched), C₁—C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; or b) R_(7B) and R_(8B) are concatenatedto form a five-membered saturated heterocycle containing one nitrogenheteroatom, the heterocycle being optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, Chd 1—C₄ alkylthio, C₁—C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁—C₄)alkyl; or c)R_(7B) and R_(8B) are concatenated to form a six-membered saturatedheterocycle containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁—C₄ alkyl,trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl, hydroxy(C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or d) R_(7B) and R_(8B) areconcatenated to form a seven-membered saturated heterocycle containingone nitrogen heteroatom, the heterocycle being optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄ alkyl)₂, —NHSO₂ R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁—C₄)alkyl; or e)R_(7B) and R_(8B) are concatenated to form an eight-membered saturatedheterocycle containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁—C₄ alkyl,trihalomethyl, Cl—C₄ alkoxy, trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄alkylthio, C₁—C₄ alkylsulfinyl, Cl—C₄ alkylsulfonyl, hydroxy(C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or f) R_(7B) and R_(8B) areconcatenated to form a saturated bicyclic heterocycle containing from6-12 carbon atoms either bridged or fused and containing one nitrogenheteroatom, the heterocycle being optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, Cl—C₄ alkylthio, C₁—C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (C₁ —C₄)alkyl, —CO₂ H, —CN, —CONHR_(1B),—NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄ alkyl)₂, —NHSO₂R₁B, —NHCOR_(1B), —NO₂,or phenyl optionally substituted with 1-3 (C₁—C₄) alkyl; or an opticalor geometric isomer thereof; or a pharmaceutically acceptable salt,N-oxide, ester, quaternary ammonium salt or prodrug thereof.
 16. Themethod of claim 10 wherein the estrogen agonist/antagonist is thecompound TSE-424 of formula Va below:

or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.
 17. The method of claim 10 wherein the estrogenagonist/antagonist is EM-652 of formula III below or is EM-800 offormula IV below:

or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quatemary ammonium salt or prodrugthereof.
 18. The method of claim 10 wherein a second compound that isuseful to prevent myocardial infarction or stroke; maintain or improvingvascular reactivity; treat acute or chronic renal failure, peripheralarterial occlusive disease, coronary artery disease, or Raynaud'sphenomenon; or lower plasma levels of Lp(a) is administered to thepatient.
 19. A kit for use by a consumer to prevent myocardialinfarction or stroke; maintain or improve vascular reactivity; treatacute or chronic renal failure, peripheral arterial occlusive disease,coronary artery disease, or Raynaud's phenomenon; or lower plasma levelsof Lp(a), the kit comprising: (a) a pharmaceutical compositioncomprising an estrogen agonist/antagonist and a pharmaceuticallyacceptable carrier, vehicle or diluent; and (b) instructions describinga method of using the pharmaceutical composition to prevent myocardialinfarction or stroke; maintain or improve vascular reactivity; treatacute or chronic renal failure, peripheral arterial occlusive disease,comary artery disease or Raynaud's phenomenon; or lower plasma levels ofLp(a).
 20. The kit of 19 wherein the estrogen agonist/antagonist is acompound of formula (I):

wherein: A is selected from CH₂ and NR; B, D and E are independentlyselected from CH and N; Y is (a) phenyl, optionally substituted with 1-3substituents independently selected from R⁴; (b) naphthyl, optionallysubstituted with 1-3 substituents independently selected from R⁴; (c)C₃—C₈ cycloalkyl, optionally substituted with 1-2 substituentsindependently selected from R ⁴; (d) C₃—C₈ cycloalkenyl, optionallysubstituted with 1-2 substituents independently selected from R ⁴; (e) afive membered heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NR²— and —S(O)_(n)-, optionallysubstituted with 1-3 substituents independently selected from R⁴; (f) asix membered heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NR²— and —S(O)_(n)- optionally substitutedwith 1-3 substituents independently selected from R⁴; or (g) a bicyclicring system consisting of a five or six membered heterocyclic ring fusedto a phenyl ring, said heterocyclic ring containing up to twoheteroatoms selected from the group consisting of —O—, —NR²— and—S(O)_(n)-, optionally substituted with 1-3 substituents independentlyselected from R⁴; Z¹ is (a) —(CH₂)_(p) W(CH₂)_(q)-; (b) —O(CH₂)_(p)CR⁵R⁶-; (c) —O(CH₂)_(p)W(CH₂)_(q)-; (d) —OCHR²CHR³-; or (e) —SCHR²CHR³-;G is (a) —NR⁷R⁸;

wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or —CH₂—;optionally fused on adjacent carbon atoms with one or two phenyl ringsand, optionally independently substituted on carbon with one to threesubstituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or (c) a bicyclicamine containing five to twelve carbon atoms, either bridged or fusedand optionally substituted with 1-3 substituents independently selectedfrom R⁴; or Z¹ and G in combination may be

W is (a) —CH₂—; (b) —CH=CH—; (c) —O—; (d) —NR²-; (e) —S(O)_(n)-;

(g) —CR²(OH)—; (h) —CONR²-; (i) —NR²CO—;

(k) —C≡C—; R is hydrogen or C₁—C₆ alkyl; R ²and R ³are independently (a)hydrogen; or (b) C₁—C₄ alkyl; R⁴ is (a) hydrogen; (b) halogen ; (C)C₁—C₆ alkyl; (d) C₁—C₄ alkoxy; (e) C₁—C₄ acyloxy; (f) C₁—C₄ alkylthio;(g) C₁—C₄ alkylsulfinyl; (h) C₁—C₄ alkylsulfonyl; (i) hydroxy (C₁—C₄)alkyl ; (j) aryl (C₁—C₄)alkyl; (k) —CO₂H; (l) —CN; (m) —CONHOR; (n)—SO₂NHR; (o) —NH₂; (p) C₁—C₄ alkylamino; (q) C₁—C₄ dialkylamino; (r)—NHSOhd 2R; (s) —NO₂; (t) -aryl; or (u) —OH; R⁵ and R⁶ are independentlyC₁—C₈ alkyl or together form a C₃—C₁₀ carbocyclic ring; R⁷ and R⁸ areindependently (a) phenyl; (b) a C₃—C₁₀ carbocyclic ring, saturated orunsaturated; (c) a C₃—C₁₀ heterocyclic ring containing up to twoheteroatoms, selected from —O—, —N— and —S—; (d) H; (e) C₁—C₆ alkyl; or(f) form a 3 to 8 membered nitrogen containing ring with R⁵ or R⁶; R⁷and R8 in either linear or ring form may optionally be substituted withup to three substituents independently selected from C₁—C₆ alkyl,halogen, alkoxy, hydroxy and carboxy; a ring formed by R⁷ and R⁸ may beoptionally fused to a phenyl ring; e is 0, 1 or 2; m is 1, 2 or 3; n is0, 1 or 2; p is 0, 1,2 or 3; q is 0, 1,2 or 3; or an optical orgeometric isomer thereof; or a pharmaceutically acceptable salt,N-oxide, ester, quaternary ammonium salt or prodrug thereof.
 21. The kitof claim 19 wherein the estrogen agonist/antagonist is a compound offormula (IA):

R⁴ is H, OH, F, or Cl; and B and E are independently selected from CHand N or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrugthereof.
 22. The kit of claim 21 wherein the estrogen agonist/antagonistis (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomerthereof; or a pharmaceutically acceptable salt, N-oxide, ester,quaternary ammonium salt, or a prodrug thereof.
 23. The kit of claim 22wherein the estrogen agonist/antagonist is in the form of a D-tartratesalt.
 24. The kit of claim 19 wherein the estrogen agonist/antagonist isa compound selected from the formulas V or VI:

wherein: R_(1B) is selected from H. OH, —O—C(O)—C₁—C₁₂ alkyl (straightchain or branched), —O—C₁—C₁₂ alkyl (straight chain or branched orcyclic), or halogens or C₁—C₄ halogenated ethers ; R_(2B), R_(3B),R_(4B), R_(5B), and R_(6B) are independently selected from H. OH,—O—C(O)—C₁—C₁₂ (straight chain or branched), —O—C₁—C₁ ₂ (straight chainor branched or cyclic), halogens, or C,—C₄ halogenated ethers, cyano,C₁—C₆ alkyl (straight chain or branched), or trifluoromethyl; X_(A) isselected from H, C_(—C) ₆ alkyl, cyano, nitro, trifluoromethyl, andhalogen; s is 2or 3; Y_(A) is the moiety:

wherein: a) R_(7B) and R_(8B) are independently selected from the groupof H, C,—C₆ alkyl, or phenyl optionally substituted by CN, C₁—C₆ alkyl(straight chain or branched), Cl—C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃; or b) R_(7B) and R_(8B) are concatenatedto form a five-membered saturated heterocycle containing one nitrogenheteroatom, the heterocycle being optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C,—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl,Cl—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁—C₄)alkyl; or c)R_(7B) and R_(8B) are concatenated to form a six-membered saturatedheterocycle containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁—C₄ alkyl,trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄alkylthio, C₁—C₄alkylsulfinyl, C₁—C₄ alkylsulfonyl, hydroxy(C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (C₁—C₄)alkyl; or d) R_(7B) and R_(8B) areconcatenated to form a seven-membered saturated heterocycle containingone nitrogen heteroatom, the heterocycle being optionally substitutedwith 1-3 substituents independently selected from the group consistingof hydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁—C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B),—NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄ alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁—C₄)alkyl; or e)R_(7B) and R_(8B) are concatenated to form an eight-membered saturatedheterocycle containing one nitrogen heteroatom, the heterocycle beingoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁—C₄ alkyl,trihalomethyl, C₁—C₄ alkoxy, trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄alkylthio, C₁—C₄ alkylsulfinyl, C₁—C₄ alkylsulfonyl, hydroxy(C₁—C₄)alkyl, —CO₂H, —CN, —CONHR_(1B), —NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄alkyl)₂, —NHSO₂R_(1B), —NHCOR_(1B), —NO₂, or phenyl optionallysubstituted with 1-3 (Cl—C₄)alkyl; or f) R_(7B) and R_(8B) areconcatenated to form a saturated bicyclic heterocycle containing from6-12 carbon atoms either bridged or fused and containing one nitrogenheteroatom, the heterocycle being optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁—C₄ alkyl, trihalomethyl, C₁—C₄ alkoxy,trihalomethoxy, C₁—C₄ acyloxy, C₁—C₄ alkylthio, C₁ 13 C₄ alkylsulfinyl,C₁—C₄ alkylsulfonyl, hydroxy (C₁—C₄)alkyl, —CO₂ H, —CN, —CONHR_(1B),—NH₂, —NH(C₁—C₄ alkyl), —N(C₁—C₄ alkyl)₂, -NHSO₂R_(1B), —NHCOR_(1B),—NO₂, or phenyl optionally substituted with 1-3 (C₁—C₄) alkyl; or anoptical or geometric isomer thereof; or a pharmaceutically acceptablesalt, N-oxide, ester, quaternary ammonium salt or prodrug thereof. 25.The kit of claim 19 wherein the estrogen agonist/antagonist is thecompound TSE-424 of formula Va below:

or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.
 26. The kit of claim 19 wherein the estrogen agonist/antagonistis EM-652 of formula III below or EM-800 of formula IV below:

or an optical or geometric isomer thereof; or a pharmaceuticallyacceptable salt, N-oxide, ester, quaternary ammonium salt or prodrugthereof.
 27. The kit of claim 19 wherein the kit further comprises anadditional compound that is useful to prevent myocardial infarction orstroke; maintain or improve vascular reactivity; treat acute or chronicrenal failure, peripheral arterial occlusive disease, coronary arterydisease or Raynaud's phenomenon; or lower plasma levels of Lp(a).